Thiazolyl-containing compounds for treating proliferative diseases

ABSTRACT

The present disclosure provides thiazolyl-containing compounds of Formula (I), (II), or (III). The compounds described herein may be able to inhibit protein kinases (e.g., Src family kinases (e.g., hemopoietic cell kinase (HCK)), Bruton&#39;s tyrosine kinase (BTK)) and may be useful in treating and/or preventing proliferative diseases (e.g., myelodysplasia, leukemia, lymphoma (e.g., Waldenström&#39;s macroglobulinemia)) and in inducing apoptosis in a cell (e.g., malignant blood cell). Also provided in the present disclosure are pharmaceutical compositions, kits, methods, and uses including or using a compound described herein.

RELATED APPLICATIONS

This application is a divisional of and claims priority under 35 U.S.C.§ 120 to U.S. application, U.S. Ser. No. 15/518,541, filed Apr. 12,2017, which is a national stage filing under 35 U.S.C. § 371 ofinternational PCT application, PCT/US2015/056899, filed Oct. 22, 2015,which claims priority under 35 U.S.C. § 119 (e) to U.S. ProvisionalApplication Ser. No. 62/067,178, filed Oct. 22, 2014, each of which isincorporated herein by reference.

GOVERNMENT SUPPORT

This invention was made with government support under grant number 2 P50CA100707-11A1 awarded by the National Institutes of Health. Thegovernment has certain rights in the invention.

BACKGROUND OF THE INVENTION

Hematological malignancies are types of cancers that affect the blood,the bone marrow, and/or the lymph nodes. Hematological malignanciesderive from either of the two major blood cell lineages: the myeloid andlymphoid lineages. The myeloid lineage normally produces granulocytes,erythrocytes, thrombocytes, macrophages, and mast cells; and thelymphoid lineage produces B, T, Natural Killer (NK), and plasma cells.Acute and chronic myelogenous leukemia, myelodysplasia, andmyeloproliferative diseases are examples of hematological malignanciesof myeloid origin; and lymphomas, lymphocytic leukemias, and myeloma areexamples of hematological malignancies of the lymphoid lineage.

Myelodysplasia, also known as myelodysplastic syndrome (MDS), is ahematological malignancy with ineffective production (or dysplasia) ofthe myeloid class of blood cells.

Lymphomas include Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL),multiple myeloma, and immunoproliferative diseases. Waldenström'smacroglobulinemia (WM) is a rare, slow-growing, non-Hodgkin lymphoma. WMis also called lymphoplasmacytic lymphoma. Lymphoplasmacytic cells arecells that are in the process of maturing from B cells to plasma cells.In WM, abnormal lymphoplasmacytic cells multiply out of control,producing large amounts of a protein called monoclonal immunoglobulin M(IgM or “macroglobulin”) antibody. High levels of IgM in the blood causehyperviscosity (thickness or gumminess).

Diffuse large B-cell lymphoma (DLBCL or DLBL) is a malignancy of Bcells. Usually DLBCL arises from normal B cells, but it can alsorepresent a malignant transformation of other types of lymphoma orleukemia. An underlying immunodeficiency is a significant risk factor.

Central nervous system (CNS) lymphoma is a rare non-Hodgkin lymphoma inwhich malignant cells from lymph tissue form in the brain, spinal cord,meninges, and/or eye (primary CNS lymphoma) or spread from other partsof the body to the brain and/or spinal cord (secondary CNS lymphoma).

Lymphomas of an immune privileged site include, but are not limited to,cerebral lymphoma, ocular lymphoma, lymphoma of the placenta, lymphomaof the fetus, and testicular lymphoma.

Marginal zone lymphomas are a group of slow-growing, non-Hodgkin B-celllymphomas presenting primarily in the marginal zone. There are threetypes of marginal zone lymphomas: Splenic marginal zone lymphoma,extranodal marginal zone B cell lymphoma (mucosa-associated lymphoidtissue (MALT) lymphoma), and nodal marginal zone B cell lymphoma (NMZL).

Leukemias are malignancies of the white blood cells (leukocytes).Chronic lymphoid leukemia (CLL) is the most common type of leukemia inadults. CLL affects B cell lymphocytes. In a subject with CLL, B cellsgrow out of control, accumulate in the bone marrow and blood, and crowdout healthy blood cells.

There is a need for novel therapies of hematological malignancies.

SUMMARY OF THE INVENTION

The present disclosure provides thiazolyl-containing compounds, such ascompounds of Formula (I), (II), or (III). In certain embodiments, thecompounds described herein are able to inhibit of protein kinases (e.g.,Src family kinases (e.g., hemopoietic cell kinase (HCK)), Bruton'styrosine kinase (BTK)). The compounds may be useful in treating and/orpreventing proliferative diseases (e.g., myelodysplasia, leukemia,lymphoma (e.g., Waldenström's macroglobulinemia)). Without wishing to bebound by any particular theory, the compounds may act by inducingapoptosis of a cell (e.g., malignant blood cell). Also provided in thepresent disclosure are pharmaceutical compositions, kits, methods, anduses including a compound described herein.

In one aspect, the present disclosure provides compounds of Formula (I):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein Ring A1, R^(A1), k, L^(A), R^(A3), RingA3, R^(A4), R^(A5), m, R^(A6), and R^(A7) are described herein.

Exemplary compounds of Formula (I) include, but are not limited to:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopic ally labeledderivatives, and prodrugs thereof.

In one aspect, the present disclosure provides compounds of Formula(II):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein Ring B1, R^(B1), p, L^(B), R^(B3), R^(B4),Ring B3, R^(B5), q, and R^(B6) are described herein.

Exemplary compounds of Formula (II) include, but are not limited to:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopic ally labeledderivatives, and prodrugs thereof.

In one aspect, the present disclosure provides compounds of Formula(III):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein Ring C1, R^(C1), r, L^(C), R^(C2), s,R^(C3), Ring C3, R^(C4), t, and R^(C5) are described herein.

Exemplary compounds of Formula (III) include, but are not limited to:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopic ally labeledderivatives, and prodrugs thereof.

In still another aspect, the present disclosure provides pharmaceuticalcompositions including a compound described herein, and optionally apharmaceutically acceptable excipient. In certain embodiments, thepharmaceutical compositions described herein include an effective amountof a compound described herein. An effective amount described herein maybe a therapeutically effective amount or prophylactically effectiveamount. The pharmaceutical composition may be useful for treating aproliferative disease in a subject in need thereof, preventing aproliferative disease in a subject in need thereof, inhibiting theactivity of a protein kinase in a subject, biological sample, tissue, orcell, and/or inducing apoptosis in a cell.

In certain embodiments, a proliferative disease described herein ismyelodysplasia, leukemia (e.g., chronic lymphocytic leukemia (CLL)),lymphoma (e.g., Waldenström's macroglobulinemia, activated B-cell (ABC)diffuse large B-cell lymphoma (DLBCL), central nervous system (CNS)lymphoma, lymphoma of an immune privileged site, testicular lymphoma, ormarginal zone lymphoma).

In certain embodiments, the subject is a mammal (e.g., human ornon-human mammal). In certain embodiments, the cell is in vitro or invivo. In certain embodiments, the cell is a malignant blood cell.

In certain embodiments, the protein kinase is a Src family kinase (e.g.,HCK) or BTK.

Another aspect of the present disclosure relates to methods of treatinga proliferative disease in a subject in need thereof.

In another aspect, the present disclosure provides methods of preventinga proliferative disease in a subject in need thereof.

In another aspect, the present disclosure provides methods of inhibitingthe activity (e.g., aberrant activity or increased activity) of aprotein kinase in a subject, biological sample, tissue, or cell. Incertain embodiments, the activity of the protein kinase is selectivelyinhibited, compared to the activity of a different protein kinase.

In yet another aspect, the present disclosure provides methods ofinducing apoptosis in a cell.

In certain embodiments, a method described herein includes administeringto the subject an effective amount of a compound or pharmaceuticalcomposition described herein. In certain embodiments, a method describedherein includes contacting a cell with an effective amount of a compoundor pharmaceutical composition described herein. In certain embodiments,a method described herein further includes administering to the subjectan additional pharmaceutical agent. In certain embodiments, a methoddescribed herein further includes contacting the cell with an additionalpharmaceutical agent. In certain embodiments, a method described hereinfurther includes performing a radiotherapy, immunotherapy, and/ortransplantation on the subject.

Another aspect of the disclosure relates to methods of screening alibrary of compounds to identify a compound that is useful in a methodof the disclosure.

Another aspect of the present disclosure relates to kits comprising acontainer with a compound or pharmaceutical composition describedherein. The kits described herein may include a single dose or multipledoses of the compound or pharmaceutical composition. The kits may beuseful in a method of the disclosure. In certain embodiments, the kitfurther includes instructions for using the compound or pharmaceuticalcomposition.

In yet another aspect, the present disclosure provides compounds andpharmaceutical compositions described herein for use in a method of thedisclosure.

The details of one or more embodiments of the disclosure are set forthherein. Other features, objects, and advantages of the disclosure willbe apparent from the Detailed Description, the Examples, and the Claims.

Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987. The disclosure is not intended to belimited in any manner by the exemplary listing of substituents describedherein.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, N Y, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The disclosure additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆.

The term “aliphatic” includes both saturated and unsaturated, straightchain (i.e., unbranched), branched, acyclic, cyclic, or polycyclicaliphatic hydrocarbons, which are optionally substituted with one ormore functional groups. As will be appreciated by one of ordinary skillin the art, “aliphatic” is intended herein to include, but is notlimited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, andcycloalkynyl moieties. Thus, the term “alkyl” includes straight,branched and cyclic alkyl groups. An analogous convention applies toother generic terms such as “alkenyl”, “alkynyl”, and the like.Furthermore, the terms “alkyl”, “alkenyl”, “alkynyl”, and the likeencompass both substituted and unsubstituted groups. In certainembodiments, “lower alkyl” is used to indicate those alkyl groups(cyclic, acyclic, substituted, unsubstituted, branched or unbranched)having 1-6 carbon atoms.

In certain embodiments, the alkyl, alkenyl, and alkynyl groups employedin the disclosure contain 1-20 aliphatic carbon atoms. In certain otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in thedisclosure contain 1-10 aliphatic carbon atoms. In yet otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in thedisclosure contain 1-8 aliphatic carbon atoms. In still otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in thedisclosure contain 1-6 aliphatic carbon atoms. In yet other embodiments,the alkyl, alkenyl, and alkynyl groups employed in the disclosurecontain 1-4 carbon atoms. Illustrative aliphatic groups thus include,but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl,cyclopropyl, —CH₂-cyclopropyl, vinyl, allyl, n-butyl, sec-butyl,isobutyl, tert-butyl, cyclobutyl, —CH₂-cyclobutyl, n-pentyl, sec-pentyl,isopentyl, tert-pentyl, cyclopentyl, —CH₂-cyclopentyl, n-hexyl,sec-hexyl, cyclohexyl, —CH₂-cyclohexyl moieties and the like, whichagain, may bear one or more substituents. Alkenyl groups include, butare not limited to, for example, ethenyl, propenyl, butenyl,1-methyl-2-buten-1-yl, and the like. Representative alkynyl groupsinclude, but are not limited to, ethynyl, 2-propynyl (propargyl),1-propynyl, and the like.

The term “alkyl” refers to a radical of a straight-chain or branchedsaturated hydrocarbon group having from 1 to 10 carbon atoms (“C₁₋₁₀alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms(“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbonatoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 7carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl group has 1to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl grouphas 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments, an alkylgroup has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In some embodiments, analkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments,an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In someembodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In someembodiments, an alkyl group has 2 to 6 carbon atoms (“C₂₋₆ alkyl”).Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl (C₂), propyl(C₃) (e.g., n-propyl, isopropyl), butyl (C₄) (e.g., n-butyl, tert-butyl,sec-butyl, iso-butyl), pentyl (C₅) (e.g., n-pentyl, 3-pentanyl, amyl,neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C₆) (e.g.,n-hexyl). Additional examples of alkyl groups include n-heptyl (C₇),n-octyl (C₈), and the like. Unless otherwise specified, each instance ofan alkyl group is independently unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents(e.g., halogen, such as F). In certain embodiments, the alkyl group isan unsubstituted C₁₋₁₀ alkyl (such as unsubstituted C₁₋₆ alkyl, e.g.,—CH₃). In certain embodiments, the alkyl group is a substituted C₁₋₁₀alkyl (such as substituted C₁₋₆ alkyl, e.g., —CF₃).

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds, and no triple bonds (“C₂₋₂₀ alkenyl”). Insome embodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents. In certainembodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl. Incertain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl. Inan alkenyl group, a C═C double bond for which the stereochemistry is notspecified (e.g., —CH═CHCH₃ or

may be an (E)- or (Z)-double bond.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds, and optionally one or more double bonds(“C₂₋₂₀ alkynyl”). In some embodiments, an alkynyl group has 2 to 10carbon atoms (“C₂₋₁₀ alkynyl”). In some embodiments, an alkynyl grouphas 2 to 9 carbon atoms (“C₂₋₉ alkynyl”). In some embodiments, analkynyl group has 2 to 8 carbon atoms (“C₂₋₈ alkynyl”). In someembodiments, an alkynyl group has 2 to 7 carbon atoms (“C₂₋₇ alkynyl”).In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C₂₋₆alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms(“C₂₋₅ alkynyl”). In some embodiments, an alkynyl group has 2 to 4carbon atoms (“C₂₋₄ alkynyl”). In some embodiments, an alkynyl group has2 to 3 carbon atoms (“C₂₋₃ alkynyl”). In some embodiments, an alkynylgroup has 2 carbon atoms (“C₂ alkynyl”). The one or more carbon-carbontriple bonds can be internal (such as in 2-butynyl) or terminal (such asin 1-butynyl). Examples of C₂₋₄ alkynyl groups include, withoutlimitation, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl(C₄), 2-butynyl (C₄), and the like. Examples of C₂₋₆ alkenyl groupsinclude the aforementioned C₂₋₄ alkynyl groups as well as pentynyl (C₅),hexynyl (C₆), and the like. Additional examples of alkynyl includeheptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified,each instance of an alkynyl group is independently optionallysubstituted, i.e., unsubstituted (an “unsubstituted alkynyl”) orsubstituted (a “substituted alkynyl”) with one or more substituents. Incertain embodiments, the alkynyl group is unsubstituted C₂₋₁₀ alkynyl.In certain embodiments, the alkynyl group is substituted C₂₋₁₀ alkynyl.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclic ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclic ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₃₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₃₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system,such as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclic ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclicring, or ring systems wherein the heterocyclic ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclic ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclic ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-10 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiiranyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, triazinanyl.Exemplary 7-membered heterocyclyl groups containing one heteroatominclude, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pielectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₋₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Unlessotherwise specified, each instance of an aryl group is independentlyoptionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) orsubstituted (a “substituted aryl”) with one or more substituents. Incertain embodiments, the aryl group is unsubstituted C₆₋₁₄ aryl. Incertain embodiments, the aryl group is substituted C₆₋₁₄ aryl.

“Aralkyl” is a subset of alkyl and aryl and refers to an optionallysubstituted alkyl group substituted by an optionally substituted arylgroup. In certain embodiments, the aralkyl is optionally substitutedbenzyl. In certain embodiments, the aralkyl is benzyl. In certainembodiments, the aralkyl is optionally substituted phenethyl. In certainembodiments, the aralkyl is phenethyl.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl, and thiophenyl.Exemplary 5-membered heteroaryl groups containing two heteroatomsinclude, without limitation, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroarylgroups containing three heteroatoms include, without limitation,triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-memberedheteroaryl groups containing four heteroatoms include, withoutlimitation, tetrazolyl. Exemplary 6-membered heteroaryl groupscontaining one heteroatom include, without limitation, pyridinyl.Exemplary 6-membered heteroaryl groups containing two heteroatomsinclude, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.Exemplary 6-membered heteroaryl groups containing three or fourheteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7-membered heteroaryl groups containing oneheteroatom include, without limitation, azepinyl, oxepinyl, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryl groups include, withoutlimitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Heteroaralkyl” is a subset of alkyl and heteroaryl and refers to anoptionally substituted alkyl group substituted by an optionallysubstituted heteroaryl group.

“Unsaturated” or “partially unsaturated” refers to a group that includesat least one double or triple bond. A “partially unsaturated” ringsystem is further intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aromatic groups (e.g., arylor heteroaryl groups). Likewise, “saturated” refers to a group that doesnot contain a double or triple bond, i.e., contains all single bonds.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, which are divalent bridging groups, are further referred tousing the suffix -ene, e.g., alkylene, alkenylene, alkynylene,carbocyclylene, heterocyclylene, arylene, and heteroarylene.

An atom, moiety, or group described herein may be unsubstituted orsubstituted, as valency permits, unless otherwise provided expressly.The term “optionally substituted” refers to substituted orunsubstituted.

A group is optionally substituted unless expressly provided otherwise.The term “optionally substituted” refers to being substituted orunsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionallysubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted”or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl,“substituted” or “unsubstituted” carbocyclyl, “substituted” or“unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or“substituted” or “unsubstituted” heteroaryl group). In general, the term“substituted”, whether preceded by the term “optionally” or not, meansthat at least one hydrogen present on a group (e.g., a carbon ornitrogen atom) is replaced with a permissible substituent, e.g., asubstituent which upon substitution results in a stable compound, e.g.,a compound which does not spontaneously undergo transformation such asby rearrangement, cyclization, elimination, or other reaction. Unlessotherwise indicated, a “substituted” group has a substituent at one ormore substitutable positions of the group, and when more than oneposition in any given structure is substituted, the substituent iseither the same or different at each position. The term “substituted” iscontemplated to include substitution with all permissible substituentsof organic compounds, any of the substituents described herein thatresults in the formation of a stable compound. The present disclosurecontemplates any and all such combinations in order to arrive at astable compound. For purposes of this disclosure, heteroatoms such asnitrogen may have hydrogen substituents and/or any suitable substituentas described herein which satisfy the valencies of the heteroatoms andresults in the formation of a stable moiety. In certain embodiments, thesubstituent is a carbon atom substituent. In certain embodiments, thesubstituent is a nitrogen atom substituent. In certain embodiments, thesubstituent is an oxygen atom substituent. In certain embodiments, thesubstituent is a sulfur atom substituent.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb)—, —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —OP(═O)(R^(aa))₂,—OP(═O)(OR^(cc))₂, —P(═O)(N(R^(bb))₂)₂, —OP(═O)(N(R^(bb))₂)₂,—NR^(bb)P(═O)(R^(aa))₂, —NR^(bb)P(═O)(OR^(cc))₂,—NR^(bb)P(═O)(N(R^(bb))₂)₂, —P(R^(cc))₂, —P(OR^(cc))₂, —P(R^(cc))₃ ⁺X⁻,—P(OR^(cc))₃ ⁺X⁻, —P(R^(cc))₄, —P(OR^(cc))₄, —OP(R^(cc))₂, —OP(R^(cc))₃⁺X⁻, —OP(OR^(cc))₂, —OP(OR^(cc))₃ ⁺X⁻, —OP(R^(cc))₄, —OP(OR^(cc))₄,—B(R^(aa))₂, —B(OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd)groups; wherein X— is a counterion;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc); each instance of R^(a)is, independently, selected from C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(aa) groups arejoined to form a 3-14 membered heterocyclyl or 5-14 membered heteroarylring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)(N(R^(cc))₂)₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(bb) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;wherein X⁻ is a counterion;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)(OR^(ee))₂,—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups, or two geminal R^(dd) substituents can be joined to form ═O or═S; wherein X⁻ is a counterion;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(ff) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₄ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)(OC₁₋₆ alkyl)₂, —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X is a counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. An anionic counterion may be monovalent (i.e.,including one formal negative charge). An anionic counterion may also bemultivalent (i.e., including more than one formal negative charge), suchas divalent or trivalent. Exemplary counterions include halide ions(e.g., F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HCO₃ ⁻, HSO₄ ⁻,sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate,p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate,naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate,ethan-1-sulfonic acid-2-sulfonate, and the like), carboxylate ions(e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, gluconate, and the like), BF₄ ⁻, PF₄ ⁻, PF₆ ⁻, AsF₆ ⁻, SbF₆⁻, B[3,5-(CF₃)₂C₆H₃]₄]⁻, B(C₆F₅)₄—, BPh₄ ⁻, Al(OC(CF₃)₃)₄ ⁻, andcarborane anions (e.g., CB₁₁H₁₂ ⁻ or (HCB₁₁Me₅Br₆)⁻). Exemplarycounterions which may be multivalent include CO₃ ²⁻, HPO₄ ²⁻, PO₄ ³⁻,B₄O₇ ²⁻, SO₄ ²⁻, S₂O₃ ²⁻, carboxylate anions (e.g., tartrate, citrate,fumarate, maleate, malate, malonate, gluconate, succinate, glutarate,adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates,aspartate, glutamate, and the like), and carboranes.

“Halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro,—Cl), bromine (bromo, —Br), or iodine (iodo, —I).

“Acyl” refers to a moiety selected from the group consisting of—C(═O)R^(aa), —CHO, —CO₂R^(aa), —C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa),—C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), or —C(═S)SR^(aa), wherein R^(aa) andR^(bb) are as defined herein.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quaternary nitrogen atoms.Exemplary nitrogen atom substituents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)(OR^(cc))₂, —P(═O)(R^(aa))₂, —P(═O)(N(R^(cc))₂)₂, C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(cc) groups attached to a nitrogen atom are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, andwherein R^(aa), R^(bb), R^(cc), and R^(dd) are as defined above.

In certain embodiments, the substituent present on a nitrogen atom is anitrogen protecting group (also referred to as an amino protectinggroup). Nitrogen protecting groups include, but are not limited to, —OH,—OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl(e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aralkyl, aryl, and heteroaryl is independently substitutedwith 0, 1, 2, 3, 4, or 5 R^(dd) groups, and wherein R^(aa), R^(bb),R^(cc) and R^(dd) are as defined herein. Nitrogen protecting groups arewell known in the art and include those described in detail inProtecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts,3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

For example, nitrogen protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g.,—C(═O)OR^(aa)) include, but are not limited to, methyl carbamate,ethylcarbamate, 9-fluorenylmethyl carbamate (Fmoc),9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethylcarbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc),vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallylcarbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate(Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g.,—S(═O)₂R^(aa)) include, but are not limited to, p-toluenesulfonamide(Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide(Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), J3-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

Exemplary oxygen atom substituents include, but are not limited to,—R^(aa), —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R, —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃ ⁺X⁻,—P(OR^(cc))₂, —P(OR^(cc))₃ ⁺X⁻, —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, and—P(═O)(N(R^(bb))₂)₂, wherein X⁻, R^(aa), R^(bb), and R^(cc) are asdefined herein. In certain embodiments, the oxygen atom substituentpresent on an oxygen atom is an oxygen protecting group (also referredto as a hydroxyl protecting group). Oxygen protecting groups are wellknown in the art and include those described in detail in ProtectingGroups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^(rd)edition, John Wiley & Sons, 1999, incorporated herein by reference.Exemplary oxygen protecting groups include, but are not limited to,methyl, t-butyloxycarbonyl (BOC or Boc), methoxylmethyl (MOM),methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate(TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec),2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutylcarbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkylp-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzylcarbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzylcarbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate,4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate,4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts).

Exemplary sulfur atom substituents include, but are not limited to,—R^(aa), —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃,—P(═O)₂R, —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and—P(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein. In certain embodiments, the sulfur atom substituent present on asulfur atom is a sulfur protecting group (also referred to as a thiolprotecting group). Sulfur protecting groups are well known in the artand include those described in detail in Protecting Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley &Sons, 1999, incorporated herein by reference.

A “hydrocarbon chain” refers to a substituted or unsubstituted divalentalkyl, alkenyl, or alkynyl group. A hydrocarbon chain includes (1) oneor more chains of carbon atoms immediately between the two radicals ofthe hydrocarbon chain; (2) optionally one or more hydrogen atoms on thechain(s) of carbon atoms; and (3) optionally one or more substituents(“non-chain substituents,” which are not hydrogen) on the chain(s) ofcarbon atoms. A chain of carbon atoms consists of consecutivelyconnected carbon atoms (“chain atoms” or “carbon units”) and does notinclude hydrogen atoms or heteroatoms. However, a non-chain substituentof a hydrocarbon chain may include any atoms, including hydrogen atoms,carbon atoms, and heteroatoms. For example, hydrocarbon chain—C^(A)H(C^(B)H₂C^(C)H₃)— includes one chain atom C^(A), one hydrogenatom on C^(A), and non-chain substituent —(C^(B)H₂C^(C)H₃). The term“C_(x) hydrocarbon chain,” wherein x is a positive integer, refers to ahydrocarbon chain that includes x number of chain atom(s) between thetwo radicals of the hydrocarbon chain. If there is more than onepossible value of x, the smallest possible value of x is used for thedefinition of the hydrocarbon chain. For example, —CH(C₂H₅)— is a C₁hydrocarbon chain, and

is a C₃ hydrocarbon chain. When a range of values is used, the meaningof the range is as described herein. For example, a C₃₋₁₀ hydrocarbonchain refers to a hydrocarbon chain where the number of chain atoms ofthe shortest chain of carbon atoms immediately between the two radicalsof the hydrocarbon chain is 3, 4, 5, 6, 7, 8, 9, or 10. A hydrocarbonchain may be saturated (e.g., —(CH₂)₄—). A hydrocarbon chain may also beunsaturated and include one or more C═C and/or C≡C bonds anywhere in thehydrocarbon chain. For instance, —CH═CH—(CH₂)₂—, —CH₂—C≡C—CH₂—, and—C≡C—CH═CH— are all examples of a unsubstituted and unsaturatedhydrocarbon chain. In certain embodiments, the hydrocarbon chain isunsubstituted (e.g., —C≡C— or —(CH₂)₄—). In certain embodiments, thehydrocarbon chain is substituted (e.g., —CH(C₂H₅)— and —CF₂—). Any twosubstituents on the hydrocarbon chain may be joined to form anoptionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl ring.For instance,

are all examples of a hydrocarbon chain. In contrast, in certainembodiments,

are not within the scope of the hydrocarbon chains described herein.When a chain atom of a C_(x) hydrocarbon chain is replaced with aheteroatom, the resulting group is referred to as a C_(x) hydrocarbonchain wherein a chain atom is replaced with a heteroatom, as opposed toa C_(x-1) hydrocarbon chain. For example,

is a C₃ hydrocarbon chain wherein one chain atom is replaced with anoxygen atom.

The term “leaving group” is given its ordinary meaning in the art ofsynthetic organic chemistry and refers to an atom or a group capable ofbeing displaced by a nucleophile. Examples of suitable leaving groupsinclude, but are not limited to, halogen (such as F, Cl, Br, or I(iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy,arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy,aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates.Exemplary leaving groups include, but are not limited to, activatedsubstituted hydroxyl groups (e.g., —OC(═O)SR^(aa), —OC(═O)R^(aa),—OCO₂R^(aa), —OC(═O)N(R^(bb))₂, —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —OC(═NR^(bb))N(R^(bb))₂, —OS(═O)R^(aa),—OSO₂R^(aa), —OP(R^(cc))₂, —OP(R^(cc))₃, —OP(═O)₂R^(aa),—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —OP(═O)₂N(R^(bb))₂, and—OP(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein). In some cases, the leaving group is a sulfonic acid ester, suchas toluenesulfonate (tosylate, —OTs), methanesulfonate (mesylate, —OMs),p-bromobenzenesulfonyloxy (brosylate, —OBs), —OS(═O)₂(CF₂)₃CF₃(nonaflate, —ONf), or trifluoromethanesulfonate (triflate, —OTf). Insome cases, the leaving group is a brosylate, such asp-bromobenzenesulfonyloxy. In some cases, the leaving group is anosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, theleaving group is a sulfonate-containing group. In some embodiments, theleaving group is a tosylate group. The leaving group may also be aphosphineoxide (e.g., formed during a Mitsunobu reaction) or an internalleaving group such as an epoxide or cyclic sulfate. Other non-limitingexamples of leaving groups are water, ammonia, alcohols, ether moieties,thioether moieties, zinc halides, magnesium moieties, diazonium salts,and copper moieties.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds describedherein include those derived from suitable inorganic and organic acidsand bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid, and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, ormalonic acid or by using other methods known in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ ⁻ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate, and aryl sulfonate.

The term “solvate” refers to forms of the compound that are associatedwith a solvent, usually by a solvolysis reaction. This physicalassociation may include hydrogen bonding. Conventional solvents includewater, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and thelike. The compounds described herein may be prepared, e.g., incrystalline form, and may be solvated. Suitable solvates includepharmaceutically acceptable solvates and further include bothstoichiometric solvates and non-stoichiometric solvates. In certaininstances, the solvate will be capable of isolation, for example, whenone or more solvent molecules are incorporated in the crystal lattice ofa crystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Representative solvates include hydrates,ethanolates, and methanolates.

The term “hydrate” refers to a compound that is associated with water.Typically, the number of the water molecules contained in a hydrate of acompound is in a definite ratio to the number of the compound moleculesin the hydrate. Therefore, a hydrate of a compound may be represented,for example, by the general formula R.x H₂O, wherein R is the compound,and x is a number greater than 0. A given compound may form more thanone type of hydrate, including, e.g., monohydrates (x is 1), lowerhydrates (x is a number greater than 0 and smaller than 1, e.g.,hemihydrates (R.0.5 H₂O)), and polyhydrates (x is a number greater than1, e.g., dihydrates (R.2H₂O) and hexahydrates (R.6H₂O)).

The term “tautomers” or “tautomeric” refers to two or moreinterconvertible compounds resulting from at least one formal migrationof a hydrogen atom and at least one change in valency (e.g., a singlebond to a double bond, a triple bond to a single bond, or vice versa).The exact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Tautomerizations (i.e., the reactionproviding a tautomeric pair) may catalyzed by acid or base. Exemplarytautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim,enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

The term “polymorphs” refers to a crystalline form of a compound (or asalt, hydrate, or solvate thereof) in a particular crystal packingarrangement. All polymorphs have the same elemental composition.Different crystalline forms usually have different X-ray diffractionpatterns, infrared spectra, melting points, density, hardness, crystalshape, optical and electrical properties, stability, and solubility.Recrystallization solvent, rate of crystallization, storage temperature,and other factors may cause one crystal form to dominate. Variouspolymorphs of a compound can be prepared by crystallization underdifferent conditions.

The term “prodrugs” refers to compounds that have cleavable groups andbecome by solvolysis or under physiological conditions the compoundsdescribed herein, which are pharmaceutically active in vivo. Suchexamples include, but are not limited to, choline ester derivatives andthe like, N-alkylmorpholine esters and the like. Other derivatives ofthe compounds described herein have activity in both their acid and acidderivative forms, but in the acid sensitive form often offer advantagesof solubility, tissue compatibility, or delayed release in the mammalianorganism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24,Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well knownto practitioners of the art, such as, for example, esters prepared byreaction of the parent acid with a suitable alcohol, or amides preparedby reaction of the parent acid compound with a substituted orunsubstituted amine, or acid anhydrides, or mixed anhydrides. Simplealiphatic or aromatic esters, amides, and anhydrides derived from acidicgroups pendant on the compounds described herein are particularprodrugs. In some cases it is desirable to prepare double ester typeprodrugs such as (acyloxy)alkyl esters or((alkoxycarbonyl)oxy)alkylesters. C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂ arylalkyl esters ofthe compounds described herein may be preferred.

The term “inhibition”, “inhibiting”, “inhibit,” or “inhibitor” refer tothe ability of a compound to reduce, slow, halt or prevent activity of aparticular biological process (e.g., activity of a bromodomain and/or abromodomain-containing protein) in a cell relative to vehicle.

When a compound, pharmaceutical composition, method, use, or kit isreferred to as “selectively,” “specifically,” or “competitively” bindinga first protein or a first chromatin, the compound, pharmaceuticalcomposition, method, use, or kit binds the first protein or the firstchromatin with a higher binding affinity (e.g., not less than about2-fold, not less than about 5-fold, not less than about 10-fold, notless than about 30-fold, not less than about 100-fold, not less thanabout 1,000-fold, or not less than about 10,000-fold) than binding asecond protein or second chromatin that is different from the firstprotein and the first chromatin. When a compound, pharmaceuticalcomposition, method, use, or kit is referred to as “selectively,”“specifically,” or “competitively” modulating (e.g., increasing orinhibiting) the activity of a bromodomain-containing protein, thecompound, pharmaceutical composition, method, use, or kit modulates theactivity of the bromodomain-containing protein to a greater extent(e.g., not less than about 2-fold, not less than about 5-fold, not lessthan about 10-fold, not less than about 30-fold, not less than about100-fold, not less than about 1,000-fold, or not less than about10,000-fold) than the activity of at least one protein that is differentfrom the bromodomain-containing protein.

The term “aberrant activity” refers to activity deviating from normalactivity. The term “increased activity” refers to activity higher thannormal activity.

The terms “composition” and “formulation” are used interchangeably.

A “subject” to which administration is contemplated refers to a human(i.e., male or female of any age group, e.g., pediatric subject (e.g.,infant, child, or adolescent) or adult subject (e.g., young adult,middle-aged adult, or senior adult)) or non-human animal. In certainembodiments, the non-human animal is a mammal (e.g., primate (e.g.,cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g.,cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g.,commercially relevant bird, such as chicken, duck, goose, or turkey)).In certain embodiments, the non-human animal is a fish, reptile, oramphibian. The non-human animal may be a male or female at any stage ofdevelopment. The non-human animal may be a transgenic animal orgenetically engineered animal. A “patient” refers to a human subject inneed of treatment of a disease. The subject may also be a plant. Incertain embodiments, the plant is a land plant. In certain embodiments,the plant is a non-vascular land plant. In certain embodiments, theplant is a vascular land plant. In certain embodiments, the plant is aseed plant. In certain embodiments, the plant is a cultivated plant. Incertain embodiments, the plant is a dicot. In certain embodiments, theplant is a monocot. In certain embodiments, the plant is a floweringplant. In some embodiments, the plant is a cereal plant, e.g., maize,corn, wheat, rice, oat, barley, rye, or millet. In some embodiments, theplant is a legume, e.g., a bean plant, e.g., soybean plant. In someembodiments, the plant is a tree or shrub.

The term “biological sample” refers to any sample including tissuesamples (such as tissue sections and needle biopsies of a tissue); cellsamples (e.g., cytological smears (such as Pap or blood smears) orsamples of cells obtained by microdissection); samples of wholeorganisms (such as samples of yeasts or bacteria); or cell fractions,fragments or organelles (such as obtained by lysing cells and separatingthe components thereof by centrifugation or otherwise). Other examplesof biological samples include blood, serum, urine, semen, fecal matter,cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus,biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy),nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccalswabs), or any material containing biomolecules that is derived from afirst biological sample.

The terms “administer,” “administering,” or “administration” refers toimplanting, absorbing, ingesting, injecting, inhaling, or otherwiseintroducing a compound described herein, or a composition thereof, in oron a subject.

The terms “treatment,” “treat,” and “treating” refer to reversing,alleviating, delaying the onset of, or inhibiting the progress of adisease described herein. In some embodiments, treatment may beadministered after one or more signs or symptoms of the disease havedeveloped or have been observed. In other embodiments, treatment may beadministered in the absence of signs or symptoms of the disease. Forexample, treatment may be administered to a susceptible subject prior tothe onset of symptoms (e.g., in light of a history of symptoms and/or inlight of exposure to a pathogen). Treatment may also be continued aftersymptoms have resolved, for example, to delay or prevent recurrence.

The terms “condition,” “disease,” and “disorder” are usedinterchangeably.

An “effective amount” of a compound described herein refers to an amountsufficient to elicit the desired biological response, i.e., treating thecondition. As will be appreciated by those of ordinary skill in thisart, the effective amount of a compound described herein may varydepending on such factors as the desired biological endpoint, thepharmacokinetics of the compound, the condition being treated, the modeof administration, and the age and health of the subject. In certainembodiments, an effective amount is a therapeutically effective amount.In certain embodiments, an effective amount is a prophylactic treatment.In certain embodiments, an effective amount is the amount of a compounddescribed herein in a single dose. In certain embodiments, an effectiveamount is the combined amounts of a compound described herein inmultiple doses.

A “therapeutically effective amount” of a compound described herein isan amount sufficient to provide a therapeutic benefit in the treatmentof a condition or to delay or minimize one or more symptoms associatedwith the condition. A therapeutically effective amount of a compoundmeans an amount of therapeutic agent, alone or in combination with othertherapies, which provides a therapeutic benefit in the treatment of thecondition. The term “therapeutically effective amount” can encompass anamount that improves overall therapy, reduces or avoids symptoms, signs,or causes of the condition, and/or enhances the therapeutic efficacy ofanother therapeutic agent.

A “prophylactically effective amount” of a compound described herein isan amount sufficient to prevent a condition, or one or more symptomsassociated with the condition or prevent its recurrence. Aprophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the condition. Theterm “prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

A “proliferative disease” refers to a disease that occurs due toabnormal growth or extension by the multiplication of cells (Walker,Cambridge Dictionary of Biology; Cambridge University Press: Cambridge,UK, 1990). A proliferative disease may be associated with: 1) thepathological proliferation of normally quiescent cells; 2) thepathological migration of cells from their normal location (e.g.,metastasis of neoplastic cells); 3) the pathological expression ofproteolytic enzymes such as the matrix metalloproteinases (e.g.,collagenases, gelatinases, and elastases); or 4) the pathologicalangiogenesis as in proliferative retinopathy and tumor metastasis.Exemplary proliferative diseases include cancers (i.e., “malignantneoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, andautoimmune diseases.

The term “angiogenesis” refers to the physiological process throughwhich new blood vessels form from pre-existing vessels. Angiogenesis isdistinct from vasculogenesis, which is the de novo formation ofendothelial cells from mesoderm cell precursors. The first vessels in adeveloping embryo form through vasculogenesis, after which angiogenesisis responsible for most blood vessel growth during normal or abnormaldevelopment. Angiogenesis is a vital process in growth and development,as well as in wound healing and in the formation of granulation tissue.However, angiogenesis is also a fundamental step in the transition oftumors from a benign state to a malignant one, leading to the use ofangiogenesis inhibitors in the treatment of cancer. Angiogenesis may bechemically stimulated by angiogenic proteins, such as growth factors(e.g., VEGF). “Pathological angiogenesis” refers to abnormal (e.g.,excessive or insufficient) angiogenesis that amounts to and/or isassociated with a disease.

The terms “neoplasm” and “tumor” are used herein interchangeably andrefer to an abnormal mass of tissue wherein the growth of the masssurpasses and is not coordinated with the growth of a normal tissue. Aneoplasm or tumor may be “benign” or “malignant,” depending on thefollowing characteristics: degree of cellular differentiation (includingmorphology and functionality), rate of growth, local invasion, andmetastasis. A “benign neoplasm” is generally well differentiated, hascharacteristically slower growth than a malignant neoplasm, and remainslocalized to the site of origin. In addition, a benign neoplasm does nothave the capacity to infiltrate, invade, or metastasize to distantsites. Exemplary benign neoplasms include, but are not limited to,lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheickeratoses, lentigos, and sebaceous hyperplasias. In some cases, certain“benign” tumors may later give rise to malignant neoplasms, which mayresult from additional genetic changes in a subpopulation of the tumor'sneoplastic cells, and these tumors are referred to as “pre-malignantneoplasms.” An exemplary pre-malignant neoplasm is a teratoma. Incontrast, a “malignant neoplasm” is generally poorly differentiated(anaplasia) and has characteristically rapid growth accompanied byprogressive infiltration, invasion, and destruction of the surroundingtissue. Furthermore, a malignant neoplasm generally has the capacity tometastasize to distant sites. The term “metastasis,” “metastatic,” or“metastasize” refers to the spread or migration of cancerous cells froma primary or original tumor to another organ or tissue and is typicallyidentifiable by the presence of a “secondary tumor” or “secondary cellmass” of the tissue type of the primary or original tumor and not ofthat of the organ or tissue in which the secondary (metastatic) tumor islocated. For example, a prostate cancer that has migrated to bone issaid to be metastasized prostate cancer and includes cancerous prostatecancer cells growing in bone tissue.

The term “cancer” refers to a class of diseases characterized by thedevelopment of abnormal cells that proliferate uncontrollably and havethe ability to infiltrate and destroy normal body tissues. See, e.g.,Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins:Philadelphia, 1990. Exemplary cancers include, but are not limited to,hematological malignancies. Additional exemplary cancers include, butare not limited to, acoustic neuroma; adenocarcinoma; adrenal glandcancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma,lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benignmonoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma);bladder cancer; breast cancer (e.g., adenocarcinoma of the breast,papillary carcinoma of the breast, mammary cancer, medullary carcinomaof the breast); brain cancer (e.g., meningioma, glioblastomas, glioma(e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchuscancer; carcinoid tumor; cervical cancer (e.g., cervicaladenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma;colorectal cancer (e.g., colon cancer, rectal cancer, colorectaladenocarcinoma); connective tissue cancer; epithelial carcinoma;ependymoma; endotheliosarcoma (e.g., Kaposi's sarcoma, multipleidiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterinecancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of theesophagus, Barrett's adenocarcinoma); Ewing's sarcoma; ocular cancer(e.g., intraocular melanoma, retinoblastoma); familiarhypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomachadenocarcinoma); gastrointestinal stromal tumor (GIST); germ cellcancer; head and neck cancer (e.g., head and neck squamous cellcarcinoma, oral cancer (e.g., oral squamous cell carcinoma), throatcancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngealcancer, oropharyngeal cancer)); heavy chain disease (e.g., alpha chaindisease, gamma chain disease, mu chain disease; hemangioblastoma;hypopharynx cancer; inflammatory myofibroblastic tumors; immunocyticamyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor,renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC),malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, smallcell lung cancer (SCLC), non-small cell lung cancer (NSCLC),adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g.,systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS);mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera(PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM)a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronicmyelocytic leukemia (CML), chronic neutrophilic leukemia (CNL),hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g.,neurofibromatosis (NF) type 1 or type 2, schwannomatosis);neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrinetumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer);ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma,ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer(e.g., pancreatic andenocarcinoma, intraductal papillary mucinousneoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget'sdisease of the penis and scrotum); pinealoma; primitive neuroectodermaltumor (PNT); plasma cell neoplasia; paraneoplastic syndromes;intraepithelial neoplasms; prostate cancer (e.g., prostateadenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer;skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA),melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g.,appendix cancer); soft tissue sarcoma (e.g., malignant fibroushistiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor(MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous glandcarcinoma; small intestine cancer; sweat gland carcinoma; synovioma;testicular cancer (e.g., seminoma, testicular embryonal carcinoma);thyroid cancer (e.g., papillary carcinoma of the thyroid, papillarythyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer;vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

The term “hematological malignancy” refers to tumors that affect blood,bone marrow, and/or lymph nodes. Exemplary hematological malignanciesinclude, but are not limited to, leukemia, such as acute lymphocyticleukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia(AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML)(e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL)(e.g., B-cell CLL, T-cell CLL)); lymphoma, such as Hodgkin lymphoma (HL)(e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g.,B-cell NHL, such as diffuse large cell lymphoma (DLCL) (e.g., diffuselarge B-cell lymphoma (DLBCL, e.g., activated B-cell (ABC) DLBCL(ABC-DLBCL))), follicular lymphoma, chronic lymphocytic leukemia/smalllymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginalzone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT)lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zoneB-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma,Waldenström's macroglobulinemia (WM, lymphoplasmacytic lymphoma), hairycell leukemia (HCL), immunoblastic large cell lymphoma, precursorB-lymphoblastic lymphoma, central nervous system (CNS) lymphoma (e.g.,primary CNS lymphoma and secondary CNS lymphoma); and T-cell NHL, suchas precursor T-lymphoblastic lymphomalleukemia, peripheral T-celllymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosisfungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma,extranodal natural killer T-cell lymphoma, enteropathy type T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplasticlarge cell lymphoma); lymphoma of an immune privileged site (e.g.,cerebral lymphoma, ocular lymphoma, lymphoma of the placenta, lymphomaof the fetus, testicular lymphoma); a mixture of one or moreleukemia/lymphoma as described above; myelodysplasia; and multiplemyeloma (MM).

The term “inflammatory disease” refers to a disease caused by, resultingfrom, or resulting in inflammation. The term “inflammatory disease” mayalso refer to a dysregulated inflammatory reaction that causes anexaggerated response by macrophages, granulocytes, and/or T-lymphocytesleading to abnormal tissue damage and/or cell death. An inflammatorydisease can be either an acute or chronic inflammatory condition and canresult from infections or non-infectious causes. Inflammatory diseasesinclude, without limitation, atherosclerosis, arteriosclerosis,autoimmune disorders, multiple sclerosis, systemic lupus erythematosus,polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis,tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis,rheumatoid arthritis, inflammatory arthritis, Sjogren's syndrome, giantcell arteritis, progressive systemic sclerosis (scleroderma), ankylosingspondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid,diabetes (e.g., Type I), myasthenia gravis, Hashimoto's thyroiditis,Graves' disease, Goodpasture's disease, mixed connective tissue disease,sclerosing cholangitis, inflammatory bowel disease, Crohn's disease,ulcerative colitis, pernicious anemia, inflammatory dermatoses, usualinterstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis,berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamativeinterstitial pneumonia, lymphoid interstitial pneumonia, giant cellinterstitial pneumonia, cellular interstitial pneumonia, extrinsicallergic alveolitis, Wegener's granulomatosis and related forms ofangiitis (temporal arteritis and polyarteritis nodosa), inflammatorydermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g.,poison ivy dermatitis), pneumonia, respiratory tract inflammation, AdultRespiratory Distress Syndrome (ARDS), encephalitis, immediatehypersensitivity reactions, asthma, hayfever, allergies, acuteanaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis,cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury),reperfusion injury, allograft rejection, host-versus-graft rejection,appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis,cervicitis, cholangitis, chorioamnionitis, conjunctivitis,dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis,myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis,osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis,pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis,salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis,urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis,vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, opticneuritis, temporal arteritis, transverse myelitis, necrotizingfasciitis, and necrotizing enterocolitis. An ocular inflammatory diseaseincludes, but is not limited to, post-surgical inflammation.

An “autoimmune disease” refers to a disease arising from aninappropriate immune response of the body of a subject againstsubstances and tissues normally present in the body. In other words, theimmune system mistakes some part of the body as a pathogen and attacksits own cells. This may be restricted to certain organs (e.g., inautoimmune thyroiditis) or involve a particular tissue in differentplaces (e.g., Goodpasture's disease which may affect the basementmembrane in both the lung and kidney). The treatment of autoimmunediseases is typically with immunosuppression, e.g., medications whichdecrease the immune response. Exemplary autoimmune diseases include, butare not limited to, glomerulonephritis, Goodpasture's syndrome,necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemiclupus erythematosis, rheumatoid arthritis, psoriatic arthritis, systemiclupus erythematosis, psoriasis, ulcerative colitis, systemic sclerosis,dermatomyositis/polymyositis, anti-phospholipid antibody syndrome,scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g.,Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjogren'ssyndrome, Crohn's disease, Reiter's syndrome, ankylosing spondylitis,Lyme disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, andcardiomyopathy.

The term “kinase” is a type of enzyme that transfers phosphate groupsfrom high energy donor molecules, such as ATP, to specific substrates,referred to as phosphorylation. Kinases are part of the larger family ofphosphotransferases. One of the largest groups of kinases are proteinkinases, which act on and modify the activity of specific proteins.Kinases are used extensively to transmit signals and control complexprocesses in cells. Various other kinases act on small molecules such aslipids, carbohydrates, amino acids, and nucleotides, either forsignaling or to prime them for metabolic pathways. Kinases are oftennamed after their substrates. More than 500 different protein kinaseshave been identified in humans. These exemplary human protein kinasesinclude, but are not limited to, AAK1, ABL, ACK, ACTR2, ACTR2B, AKT1,AKT2, AKT3, ALK, ALK1, ALK2, ALK4, ALK7, AMPKa1, AMPKa2, ANKRD3, ANPa,ANPb, ARAF, ARAFps, ARG, AurA, AurAps1, AurAps2, AurB, AurBps1, AurC,AXL, BARK1, BARK2, BIKE, BLK, BMPR1A, BMPR1Aps1, BMPR1Aps2, BMPR1B,BMPR2, BMX, BRAF, BRAFps, BRK, BRSK1, BRSK2, BTK, BUB1, BUBR1, CaMK1a,CaMK1b, CaMK1d, CaMK1g, CaMK2a, CaMK2b, CaMK2d, CaMK2g, CaMK4, CaMKK1,CaMKK2, caMLCK, CASK, CCK4, CCRK, CDC2, CDC7, CDK10, CDK11, CDK2, CDK3,CDK4, CDK4ps, CDK5, CDK5ps, CDK6, CDK7, CDK7ps, CDK8, CDK8ps, CDK9,CDKL1, CDKL2, CDKL3, CDKL4, CDKL5, CGDps, CHED, CHK1, CHK2, CHK2ps1,CHK2ps2, CK1a, CK1a2, CK1aps1, CK1aps2, CK1aps3, CK1d, CK1e, CK1g1,CK1g2, CK1g2ps, CK1g3, CK2a1, CK2a1-rs, CK2a2, CLIK1, CLIK1L, CLK1,CLK2, CLK2ps, CLK3, CLK3ps, CLK4, COT, CRIK, CRK7, CSK, CTK, CYGD, CYGF,DAPK1, DAPK2, DAPK3, DCAMKL1, DCAMKL2, DCAMKL3, DDR1, DDR2, DLK, DMPK1,DMPK2, DRAK1, DRAK2, DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, EGFR, EphA1,EphA10, EphA2, EphA3, EphA4, EphA5, EphA6, EphA7, EphA8, EphB1, EphB2,EphB3, EphB4, EphB6, Erk1, Erk2, Erk3, Erk3ps, Erk3ps2, Erk3ps3,Erk3ps4, Erk4, Erk5, Erk7, FAK, FER, FERps, FES, FGFR1, FGFR2, FGFR3,FGFR4, FGR, FLT1, FLT1ps, FLT3, FLT4, FMS, FRK, Fused, FYN, GAK, GCK,GCN2, GCN22, GPRK4, GPRK5, GPRK6, GPRK6ps, GPRK7, GSK3A, GSK3B, Haspin,HCK, HER2/ErbB2, HER3/ErbB3, HER4/ErbB4, HH498, HIPK1, HIPK2, HIPK3,HIPK4, HPK1, HRI, HRIps, HSER, HUNK, ICK, IGF1R, IKKa, IKKb, IKKe, ILK,INSR, IRAK1, IRAK2, IRAK3, IRAK4, IRE1, IRE2, IRR, ITK, JAK1, JAK2,JAK3, JNK1, JNK2, JNK3, KDR, KHS1, KHS2, KIS, KIT, KSGCps, KSR1, KSR2,LATS1, LATS2, LCK, LIMK1, LIMK2, LIMK2ps, LKB1, LMR1, LMR2, LMR3, LOK,LRRK1, LRRK2, LTK, LYN, LZK, MAK, MAP2K1, MAP2K1ps, MAP2K2, MAP2K2ps,MAP2K3, MAP2K4, MAP2K5, MAP2K6, MAP2K7, MAP3K1, MAP3K2, MAP3K3, MAP3K4,MAP3K5, MAP3K6, MAP3K7, MAP3K8, MAPKAPK2, MAPKAPK3, MAPKAPK5,MAPKAPKps1, MARK1, MARK2, MARK3, MARK4, MARKps01, MARKps02, MARKps03,MARKps04, MARKps05, MARKps07, MARKps08, MARKps09, MARKps10, MARKps11,MARKps12, MARKps13, MARKps15, MARKps16, MARKps17, MARKps18, MARKps19,MARKps20, MARKps21, MARKps22, MARKps23, MARKps24, MARKps25, MARKps26,MARKps27, MARKps28, MARKps29, MARKps30, MAST1, MAST2, MAST3, MAST4,MASTL, MELK, MER, MET, MISR2, MLK1, MLK2, MLK3, MLK4, MLKL, MNK1,MNK1ps, MNK2, MOK, MOS, MPSK1, MPSK1ps, MRCKa, MRCKb, MRCKps, MSK1,MSK12, MSK2, MSK22, MSSK1, MST1, MST2, MST3, MST3ps, MST4, MUSK, MYO3A,MYO3B, MYT1, NDR1, NDR2, NEK1, NEK10, NEK11, NEK2, NEK2ps1, NEK2ps2,NEK2ps3, NEK3, NEK4, NEK4ps, NEK5, NEK6, NEK7, NEK8, NEK9, NIK, NIM1,NLK, NRBP1, NRBP2, NuaK1, NuaK2, Obscn, Obscn2, OSR1, p38a, p38b, p38d,p38g, p70S6K, p70S6Kb, p70S6Kps1, p70S6Kps2, PAK1, PAK2, PAK2ps, PAK3,PAK4, PAK5, PAK6, PASK, PBK, PCTAIRE1, PCTAIRE2, PCTAIRE3, PDGFRa,PDGFRb, PDK1, PEK, PFTAIRE1, PFTAIRE2, PHKg1, PHKg1ps1, PHKg1ps2,PHKg1ps3, PHKg2, PIK3R4, PIM1, PIM2, PIM3, PINK1, PIP4K2C, PITSLRE,PKACa, PKACb, PKACg, PKCa, PKCb, PKCd, PKCe, PKCg, PKCh, PKCi, PKCips,PKCt, PKCz, PKD1, PKD2, PKD3, PKG1, PKG2, PKN1, PKN2, PKN3, PKR, PLK1,PLK1ps1, PLK1ps2, PLK2, PLK3, PLK4, PRKX, PRKXps, PRKY, PRP4, PRP4ps,PRPK, PSKH1, PSKH1ps, PSKH2, PYK2, QIK, QSK, RAF1, RAF1ps, RET, RHOK,RIPK1, RIPK2, RIPK3, RNAseL, ROCK1, ROCK2, RON, ROR1, ROR2, ROS, RSK1,RSK12, RSK2, RSK22, RSK3, RSK32, RSK4, RSK42, RSKL1, RSKL2, RYK, RYKps,SAKps, SBK, SCYL1, SCYL2, SCYL2ps, SCYL3, SGK, SgK050ps, SgK069, SgK071,SgK085, SgK110, SgK196, SGK2, SgK223, SgK269, SgK288, SGK3, SgK307,SgK384ps, SgK396, SgK424, SgK493, SgK494, SgK495, SgK496, SIK (e.g.,SIK1, SIK2), skMLCK, SLK, Slob, smMLCK, SNRK, SPEG, SPEG2, SRC, SRM,SRPK1, SRPK2, SRPK2ps, SSTK, STK33, STK33ps, STLK3, STLK5, STLK6,STLK6ps1, STLK6-rs, SuRTK106, SYK, TAK1, TAO1, TAO2, TAO3, TBCK, TBK1,TEC, TESK1, TESK2, TGFbR1, TGFbR2, TIE1, TIE2, TLK1, TLK1ps, TLK2,TLK2ps1, TLK2ps2, TNK1, Trad, Trb1, Trb2, Trb3, Trio, TRKA, TRKB, TRKC,TSSK1, TSSK2, TSSK3, TSSK4, TSSKps1, TSSKps2, TTBK1, TTBK2, TTK, TTN,TXK, TYK2, TYK22, TYRO3, TYRO3ps, ULK1, ULK2, ULK3, ULK4, VACAMKL, VRK1,VRK2, VRK3, VRK3ps, Wee1, Wee1B, Wee1Bps, Wee1ps1, Wee1ps2, Wnk1, Wnk2,Wnk3, Wnk4, YANK1, YANK2, YANK3, YES, YESps, YSK1, ZAK, ZAP70, ZC1/HGK,ZC2/TNIK, ZC3/MINK, and ZC4/NRK. In certain embodiments, the proteinkinase is a protein kinase shown in Table 2 or Table 3.

The term “SRC family kinase” refers to a family of non-receptor tyrosineprotein kinases that includes nine members: SRCA subfamily that includesc-SRC (proto-oncogene tyrosine-protein kinase SRC), YES (proto-oncogenetyrosine-protein kinase Yes), FYN (proto-oncogene tyrosine-proteinkinase FYN), and FGR (Gardner-Rasheed feline sarcoma viral (v-FGR)oncogene homolog); SRCB subfamily that includes LCK (lymphocyte-specificprotein tyrosine kinase), HCK (tyrosine-protein kinase HCK, hemopoieticcell kinase), BLK (tyrosine-protein kinase BLK), and LYN(tyrosine-protein kinase LYN); and FRK (Fyn-related kinase).

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

The present disclosure provides thiazolyl-containing compounds, such ascompounds of Formula (I), (II), or (III). In certain embodiments, thecompounds described herein are able to inhibit protein kinases (e.g.,Src family kinases (e.g., hemopoietic cell kinase (HCK)), Bruton'styrosine kinase (BTK)). Therefore, the compounds may be useful intreating and/or preventing proliferative diseases (e.g., myelodysplasia,leukemia, lymphoma (e.g., Waldenström's macroglobulinemia)). Thecompounds may act by inducing apoptosis in a cell (e.g., malignant bloodcell). Also provided in the present disclosure are pharmaceuticalcompositions, kits, methods, and uses including a compound describedherein.

Compounds

One aspect of the present disclosure relates to the compounds describedherein. The compounds described herein are thiazolyl-containingcompounds that may be useful in treating and/or preventing proliferativediseases in a subject, inhibiting the activity of a protein kinase(e.g., HCK, BTK) in a subject, biological sample, tissue, or cell,and/or inducing apoptosis in a cell. In certain embodiments, a compounddescribed herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,stereoisomer, isotopically labeled derivative, or prodrug thereof. Incertain embodiments, a compound described herein is a compound ofFormula (I), or a pharmaceutically acceptable salt thereof. In certainembodiments, a compound described herein is a compound of Formula (II),or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments, a compound described herein isa compound of Formula (II), or a pharmaceutically acceptable saltthereof. In certain embodiments, a compound described herein is acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer,isotopically labeled derivative, or prodrug thereof. In certainembodiments, a compound described herein is a compound of Formula (III),or a pharmaceutically acceptable salt thereof.

Compounds of Formula (I)

In certain embodiments, a compound described herein is of Formula (I):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof, wherein:

each instance of R^(A1) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(a), —N(R^(a))₂,—SR^(a), —CN, —SCN, —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a),—C(═NR^(a))N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂,—NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a), —NR^(a)C(═O)N(R^(a))₂,—OC(═O)R^(a), —OC(═O)OR^(a), or —OC(═O)N(R^(a))₂;

each instance of R^(a) is independently hydrogen, substituted orunsubstituted acyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two instancesof R^(a) are joined to form a substituted or unsubstituted, heterocyclicring, or substituted or unsubstituted, heteroaryl ring;

k is 0, 1, 2, 3, 4, or 5;

L^(A) is —C(═O)—NR^(A2)— or —NR^(A2)—C(═O)—, wherein R^(A2) is hydrogen,substituted or unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group;

R^(A3) is hydrogen, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —OR^(a), —N(R^(a))₂, —SR^(a),—CN, —SCN, —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a), —C(═NR^(a))N(R^(a))₂,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂, —NR^(a)C(═O)R^(a),—NR^(a)C(═O)OR^(a), —NR^(a)C(═O)N(R^(a))₂, —OC(═O)R^(a), —OC(═O)OR^(a),or —OC(═O)N(R^(a))₂;

R^(A4) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group;

each instance of R^(A5) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(a), —N(R^(a))₂,—SR^(a), —CN, —SCN, —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a),—C(═NR^(a))N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂,—NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a), —NR^(a)C(═O)N(R^(a))₂,—OC(═O)R^(a), —OC(═O)OR^(a), or —OC(═O)N(R^(a))₂;

m is 0, 1, or 2;

R^(A6) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group; and

R^(A7) is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heteroaryl, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)N(R^(a))₂, or a nitrogen protecting group.

Formula (I) includes as Ring A1 a phenyl ring that is unsubstituted(e.g., when k is 0) or substituted (e.g., when k is 1, 2, 3, 4, or 5)with one or more substituents R^(A1). In certain embodiments, Ring A1 isof the formula:

In certain embodiments, Ring A1 is of the formula:

In certain embodiments, Ring A1 is of the formula:

R^(A1), wherein each instance of R^(A1) is independently substituted orunsubstituted alkyl (e.g., substituted or unsubstituted C₁₋₆ alkyl, suchas —CH₃, —CF₃, Bn, unsubstituted ethyl, perfluoroethyl, unsubstitutedpropyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl) orhalogen (e.g., F, Cl, Br, or I). In certain embodiments, Ring A1 is ofthe formula:

In certain embodiments, Ring A1 is of the formula:

In Formula (I), Ring A1 may include one or more substituents R^(A1). Incertain embodiments, all instances of R^(A1) are the same. In certainembodiments, two instances of R^(A1) are different from each other. Incertain embodiments, at least one instance of R^(A1) is halogen (e.g.,F, Cl, Br, or I). In certain embodiments, at least one instance ofR^(A1) is substituted or unsubstituted alkyl (e.g., substituted orunsubstituted C₁₋₆ alkyl). In certain embodiments, at least one instanceof R^(A1) is —CH₃. In certain embodiments, at least one instance ofR^(A1) is —CF₃, Bn, unsubstituted ethyl, perfluoroethyl, unsubstitutedpropyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl. Incertain embodiments, at least one instance of R^(A1) is substituted orunsubstituted alkenyl (e.g., substituted or unsubstituted C₂₋₆ alkenyl).In certain embodiments, at least one instance of R^(A1) is substitutedor unsubstituted alkynyl (e.g., substituted or unsubstituted C₁₋₆alkynyl). In certain embodiments, at least one instance of R^(A1) issubstituted or unsubstituted carbocyclyl (e.g., substituted orunsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero,one, or two double bonds in the carbocyclic ring system). In certainembodiments, at least one instance of R^(A1) is substituted orunsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to9-membered, monocyclic heterocyclyl comprising zero, one, or two doublebonds in the heterocyclic ring system, wherein one, two, or three atomsin the heterocyclic ring system are independently nitrogen, oxygen, orsulfur). In certain embodiments, at least one instance of R^(A1) issubstituted or unsubstituted aryl (e.g., substituted or unsubstituted,6- to 10-membered aryl). In certain embodiments, at least one instanceof R^(A1) is substituted or unsubstituted phenyl. In certainembodiments, at least one instance of R^(A1) is substituted orunsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to6-membered, monocyclic heteroaryl, wherein one, two, three, or fouratoms in the heteroaryl ring system are independently nitrogen, oxygen,or sulfur). In certain embodiments, at least one instance of R^(A1) is—OR^(a) (e.g., —OH, —O(substituted or unsubstituted C₁₋₆ alkyl) (e.g.,—OMe, —OEt, —OPr, —OBu, or —OBn), or —O(substituted or unsubstitutedphenyl) (e.g., —OPh)). In certain embodiments, at least one instance ofR^(A1) is —SR^(a) (e.g., —SH, —S(substituted or unsubstituted C₁₋₆alkyl) (e.g., —SMe, —SEt, —SPr, —SBu, or —SBn), or —S(substituted orunsubstituted phenyl) (e.g., —SPh)). In certain embodiments, at leastone instance of R^(A1) is —N(R^(a))₂ (e.g., —NH₂, —NH(substituted orunsubstituted C₁₋₆ alkyl) (e.g., —NHMe), or —N(substituted orunsubstituted C₁₋₆ alkyl)-(substituted or unsubstituted C₁₋₆ alkyl)(e.g., —NMe₂)). In certain embodiments, at least one instance of R^(A1)is —CN, —SCN, or —NO₂. In certain embodiments, at least one instance ofR^(A1) is —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a), or —C(═NR^(a))N(R^(a))₂.In certain embodiments, at least one instance of R^(A1) is —C(═O)R^(a)(e.g., —C(═O)(substituted or unsubstituted alkyl) or —C(═O)(substitutedor unsubstituted phenyl)), —C(═O)OR^(a) (e.g., —C(═O)O(substituted orunsubstituted alkyl) or —C(═O)O(substituted or unsubstituted phenyl)),or —C(═O)N(R^(a))₂ (e.g., —C(═O)NH₂, —C(═O)NH(substituted orunsubstituted alkyl), —C(═O)NH(substituted or unsubstituted phenyl),—C(═O)N(substituted or unsubstituted alkyl)-(substituted orunsubstituted alkyl), or —C(═O)N(substituted or unsubstitutedphenyl)-(substituted or unsubstituted alkyl)). In certain embodiments,at least one instance of R^(A1) is —NR^(a)C(═O)R^(a),—NR^(a)C(═O)OR^(a), or —NR^(a)C(═O)N(R^(a))₂. In certain embodiments, atleast one instance of R^(A1) is —OC(═O)R^(a), —OC(═O)OR^(a), or—OC(═O)N(R^(a))₂.

When Formula (I) includes two or more instances of substituent R^(a),any two instances of R^(a) may be the same or different from each other.In certain embodiments, at least one instance of R^(a) is H. In certainembodiments, each instance of R^(a) is H. In certain embodiments, atleast one instance of R^(a) is substituted or unsubstituted acyl (e.g.,acetyl). In certain embodiments, at least one instance of R^(a) issubstituted or unsubstituted alkyl (e.g., substituted or unsubstitutedC₁₋₆ alkyl). In certain embodiments, at least one instance of R^(a) is—CH₃. In certain embodiments, at least one instance of R^(a) is —CF₃,Bn, unsubstituted ethyl, perfluoroethyl, unsubstituted propyl,perfluoropropyl, unsubstituted butyl, or perfluorobutyl. In certainembodiments, at least one instance of R^(a) is substituted orunsubstituted alkenyl (e.g., substituted or unsubstituted C₂₋₆ alkenyl).In certain embodiments, at least one instance of R^(a) is substituted orunsubstituted alkynyl (e.g., substituted or unsubstituted C₁₋₆ alkynyl).In certain embodiments, at least one instance of R^(a) is substituted orunsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to7-membered, monocyclic carbocyclyl comprising zero, one, or two doublebonds in the carbocyclic ring system). In certain embodiments, at leastone instance of R^(a) is substituted or unsubstituted heterocyclyl(e.g., substituted or unsubstituted, 3- to 9-membered, monocyclicheterocyclyl comprising zero, one, or two double bonds in theheterocyclic ring system, wherein one, two, or three atoms in theheterocyclic ring system are independently nitrogen, oxygen, or sulfur).In certain embodiments, at least one instance of R^(a) is substituted orunsubstituted aryl (e.g., substituted or unsubstituted, 6- to10-membered aryl). In certain embodiments, at least one instance ofR^(a) is substituted or unsubstituted phenyl. In certain embodiments, atleast one instance of R^(a) is substituted or unsubstituted heteroaryl(e.g., substituted or unsubstituted, 5- to 6-membered, monocyclicheteroaryl, wherein one, two, three, or four atoms in the heteroarylring system are independently nitrogen, oxygen, or sulfur). In certainembodiments, at least one instance of R^(a) is a nitrogen protectinggroup (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl,acetyl, or Ts) when attached to a nitrogen atom. In certain embodiments,R^(a) is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS,TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) whenattached to an oxygen atom. In certain embodiments, R^(a) is a sulfurprotecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to asulfur atom. In certain embodiments, two instances of R^(a) are joinedto form a substituted or unsubstituted, heterocyclic ring (e.g.,substituted or unsubstituted, 5- to 6-membered, monocyclic heterocyclicring comprising zero, one, or two double bonds in the heterocyclic ringsystem, wherein one, two, or three atoms in the heterocyclic ring systemare independently nitrogen, oxygen, or sulfur). In certain embodiments,two instances of R^(a) are joined to form a substituted or unsubstitutedheteroaryl ring (e.g., substituted or unsubstituted, 5- to 6-membered,monocyclic heteroaryl ring, wherein one, two, three, or four atoms inthe heteroaryl ring system are independently nitrogen, oxygen, orsulfur).

In certain embodiments, k is 0. In certain embodiments, k is 1. Incertain embodiments, k is 2. In certain embodiments, k is 3. In certainembodiments, k is 4. In certain embodiments, k is 5.

In certain embodiments, k is 1; and R^(A1) is substituted orunsubstituted alkyl (e.g., substituted or unsubstituted C₁₋₆ alkyl, suchas —CH₃, —CF₃, Bn, unsubstituted ethyl, perfluoroethyl, unsubstitutedpropyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl) orhalogen (e.g., F, Cl, Br, or I). In certain embodiments, k is 2; andeach of the two instances of R^(A1) is independently substituted orunsubstituted alkyl (e.g., substituted or unsubstituted C₁₋₆ alkyl, suchas —CH₃, —CF₃, Bn, unsubstituted ethyl, perfluoroethyl, unsubstitutedpropyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl) orhalogen (e.g., F, Cl, Br, or I).

Formula (I) includes divalent linker L^(A) connecting Ring A1 to thethiazolyl ring. In certain embodiments, L^(A) is —C(═O)—N(R^(A2))—(e.g., —C(═O)—NH—). In certain embodiments, L^(A) is —N(R^(A2))—C(═O)—(e.g., —NH—C(═O)—).

In certain embodiments, R^(A2) is H. In certain embodiments, R^(A2) issubstituted or unsubstituted C₁₋₆ alkyl (e.g., —CH₃, Bn, —CF₃,unsubstituted ethyl, perfluoroethyl, unsubstituted propyl,perfluoropropyl, unsubstituted butyl, or perfluorobutyl). In certainembodiments, R^(A2) is a nitrogen protecting group (e.g., Bn, Boc, Cbz,Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

The thiazolyl ring of Formula (I) includes substituent R^(A3). Incertain embodiments, R^(A3) is H. In certain embodiments, R^(A3) ishalogen (e.g., F, Cl, Br, or I). In certain embodiments, R^(A3) issubstituted or unsubstituted alkyl (e.g., substituted or unsubstitutedC₁₋₆ alkyl). In certain embodiments, R^(A3) is —CH₃. In certainembodiments, R^(A3) is —CF₃, Bn, unsubstituted ethyl, perfluoroethyl,unsubstituted propyl, perfluoropropyl, unsubstituted butyl, orperfluorobutyl. In certain embodiments, R^(A3) is substituted orunsubstituted alkenyl (e.g., substituted or unsubstituted C₂₋₆ alkenyl).In certain embodiments, R^(A3) is substituted or unsubstituted alkynyl(e.g., substituted or unsubstituted C₁₋₆ alkynyl). In certainembodiments, R^(A3) is substituted or unsubstituted carbocyclyl (e.g.,substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclylcomprising zero, one, or two double bonds in the carbocyclic ringsystem). In certain embodiments, R^(A3) is substituted or unsubstitutedheterocyclyl (e.g., substituted or unsubstituted, 3- to 9-membered,monocyclic heterocyclyl comprising zero, one, or two double bonds in theheterocyclic ring system, wherein one, two, or three atoms in theheterocyclic ring system are independently nitrogen, oxygen, or sulfur).In certain embodiments, R^(A3) is substituted or unsubstituted aryl(e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certainembodiments, R^(A3) is substituted or unsubstituted phenyl. In certainembodiments, R^(A3) is substituted or unsubstituted heteroaryl (e.g.,substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl,wherein one, two, three, or four atoms in the heteroaryl ring system areindependently nitrogen, oxygen, or sulfur). In certain embodiments,R^(A3) is —OR^(a) (e.g., —OH, —O(substituted or unsubstituted C₁₋₆alkyl) (e.g., —OMe, —OEt, —OPr, —OBu, or —OBn), or —O(substituted orunsubstituted phenyl) (e.g., —OPh)). In certain embodiments, R^(A3) is—SR^(a) (e.g., —SH, —S(substituted or unsubstituted C₁₋₆ alkyl) (e.g.,—SMe, —SEt, —SPr, —SBu, or —SBn), or —S(substituted or unsubstitutedphenyl) (e.g., —SPh)). In certain embodiments, R^(A3) is —N(R^(a))₂(e.g., —NH₂, —NH(substituted or unsubstituted C₁₋₆ alkyl) (e.g., —NHMe),or —N(substituted or unsubstituted C₁₋₆ alkyl)-(substituted orunsubstituted C₁₋₆ alkyl) (e.g., —NMe₂)). In certain embodiments, R^(A3)is —CN, —SCN, or —NO₂. In certain embodiments, R^(A3) is—C(═NR^(a))R^(a), —C(═NR^(a))OR^(a), or —C(═NR^(a))N(R^(a))₂. In certainembodiments, R^(A3) is —C(═O)R^(a) (e.g., —C(═O)(substituted orunsubstituted alkyl) or —C(═O)(substituted or unsubstituted phenyl)),—C(═O)OR^(a) (e.g., —C(═O)O(substituted or unsubstituted alkyl) or—C(═O)O(substituted or unsubstituted phenyl)), or —C(═O)N(R^(a))₂ (e.g.,—C(═O)NH₂, —C(═O)NH(substituted or unsubstituted alkyl),—C(═O)NH(substituted or unsubstituted phenyl), —C(═O)N(substituted orunsubstituted alkyl)-(substituted or unsubstituted alkyl), or—C(═O)N(substituted or unsubstituted phenyl)-(substituted orunsubstituted alkyl)). In certain embodiments, R^(A3) is—NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a), or —NR^(a)C(═O)N(R^(a))₂. Incertain embodiments, R^(A3) is —OC(═O)R^(a), —OC(═O)OR^(a), or—OC(═O)N(R^(a))₂.

Formula (I) includes substituent R^(A4) on a nitrogen atom attached tothe thiazolyl ring. In certain embodiments, R^(A4) is H. In certainembodiments, R^(A4) is substituted or unsubstituted C₁₋₆ alkyl (e.g.,—CH₃, Bn, —CF₃, unsubstituted ethyl, perfluoroethyl, unsubstitutedpropyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl). Incertain embodiments, R^(A4) is a nitrogen protecting group (e.g., Bn,Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

Formula (I) includes as Ring A3 a pyrimidinyl ring that is unsubstituted(e.g., when m is 0) or substituted (e.g., when m is 1 or 2) with one ormore substituents R^(A5). In certain embodiments, Ring A3 is of theformula:

In certain embodiments, Ring A3 is of the formula:

wherein R^(A5) is substituted or unsubstituted alkyl (e.g., substitutedor unsubstituted C₁₋₆ alkyl, such as —CH₃, —CF₃, Bn, unsubstitutedethyl, perfluoroethyl, unsubstituted propyl, perfluoropropyl,unsubstituted butyl, or perfluorobutyl). In certain embodiments, Ring A3is of the formula:

wherein R^(A5) is C₁₋₆ alkyl substituted independently with at least onesubstituted or unsubstituted heterocyclyl (e.g., substituted orunsubstituted, 3- to 9-membered, monocyclic heterocyclyl comprisingzero, one, or two double bonds in the heterocyclic ring system, whereinone, two, or three atoms in the heterocyclic ring system areindependently nitrogen, oxygen, or sulfur). In certain embodiments, RingA3 is of the formula:

In certain embodiments, Ring A3 is of the formula:

In certain embodiments, Ring A3 is of the formula:

In Formula (I), Ring A3 may include one or two substituents R^(A5). Incertain embodiments, two instances of R^(A5) are the same. In certainembodiments, two instances of R^(A5) are different from each other. Incertain embodiments, at least one instance of R^(A5) is halogen (e.g.,F, Cl, Br, or I). In certain embodiments, at least one instance ofR^(A5) is substituted or unsubstituted alkyl (e.g., substituted orunsubstituted C₁₋₆ alkyl). In certain embodiments, at least one instanceof R^(A5) is —CH₃. In certain embodiments, at least one instance ofR^(A5) is —CF₃, Bn, unsubstituted ethyl, perfluoroethyl, unsubstitutedpropyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl. Incertain embodiments, at least one instance of R^(A5) is C₁₋₆ alkylsubstituted with at least one substituted or unsubstituted heterocyclyl(e.g., substituted or unsubstituted, 3- to 9-membered, monocyclicheterocyclyl comprising zero, one, or two double bonds in theheterocyclic ring system, wherein one, two, or three atoms in theheterocyclic ring system are independently nitrogen, oxygen, or sulfur).In certain embodiments, at least one instance of R^(A5) is methylsubstituted at least with substituted or unsubstituted oxetanyl,substituted or unsubstituted azetidinyl, substituted or unsubstitutedtetrahydrofuranyl, substituted or unsubstituted pyrrolidinyl,substituted or unsubstituted tetrahydropyranyl, substituted orunsubstituted piperidinyl, substituted or unsubstituted morpholinyl, orsubstituted or unsubstituted piperazinyl. In certain embodiments, atleast one instance of R^(A5) is of the formula:

In certain embodiments, at least one instance of R^(A5) is substitutedor unsubstituted alkenyl (e.g., substituted or unsubstituted C₂₋₆alkenyl). In certain embodiments, at least one instance of R^(A5) issubstituted or unsubstituted alkynyl (e.g., substituted or unsubstitutedC₁₋₆ alkynyl). In certain embodiments, at least one instance of R^(A5)is substituted or unsubstituted carbocyclyl (e.g., substituted orunsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero,one, or two double bonds in the carbocyclic ring system). In certainembodiments, at least one instance of R^(A5) is substituted orunsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to9-membered, monocyclic heterocyclyl comprising zero, one, or two doublebonds in the heterocyclic ring system, wherein one, two, or three atomsin the heterocyclic ring system are independently nitrogen, oxygen, orsulfur). In certain embodiments, at least one instance of R^(A5) issubstituted or unsubstituted aryl (e.g., substituted or unsubstituted,6- to 10-membered aryl). In certain embodiments, at least one instanceof R^(A5) is substituted or unsubstituted phenyl. In certainembodiments, at least one instance of R^(A5) is substituted orunsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to6-membered, monocyclic heteroaryl, wherein one, two, three, or fouratoms in the heteroaryl ring system are independently nitrogen, oxygen,or sulfur). In certain embodiments, at least one instance of R^(A5) is—OR^(a) (e.g., —OH, —O(substituted or unsubstituted C₁₋₆ alkyl) (e.g.,—OMe, —OEt, —OPr, —OBu, or —OBn), or —O(substituted or unsubstitutedphenyl) (e.g., —OPh)). In certain embodiments, at least one instance ofR^(A5) is —SR^(a) (e.g., —SH, —S(substituted or unsubstituted C₁₋₆alkyl) (e.g., —SMe, —SEt, —SPr, —SBu, or —SBn), or —S(substituted orunsubstituted phenyl) (e.g., —SPh)). In certain embodiments, at leastone instance of R^(A5) is —N(R^(a))₂ (e.g., —NH₂, —NH(substituted orunsubstituted C₁₋₆ alkyl) (e.g., —NHMe), or —N(substituted orunsubstituted C₁₋₆ alkyl)-(substituted or unsubstituted C₁₋₆ alkyl)(e.g., —NMe₂)). In certain embodiments, at least one instance of R^(A5)is —CN, —SCN, or —NO₂. In certain embodiments, at least one instance ofR^(A5) is —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a), or —C(═NR^(a))N(R^(a))₂.In certain embodiments, at least one instance of R^(A5) is —C(═O)R^(a)(e.g., —C(═O)(substituted or unsubstituted alkyl) or —C(═O)(substitutedor unsubstituted phenyl)), —C(═O)OR^(a) (e.g., —C(═O)O(substituted orunsubstituted alkyl) or —C(═O)O(substituted or unsubstituted phenyl)),or —C(═O)N(R^(a))₂ (e.g., —C(═O)NH₂, —C(═O)NH(substituted orunsubstituted alkyl), —C(═O)NH(substituted or unsubstituted phenyl),—C(═O)N(substituted or unsubstituted alkyl)-(substituted orunsubstituted alkyl), or —C(═O)N(substituted or unsubstitutedphenyl)-(substituted or unsubstituted alkyl)). In certain embodiments,at least one instance of R^(A5) is —NR^(a)C(═O)R^(a),—NR^(a)C(═O)OR^(a), or —NR^(a)C(═O)N(R^(a))₂. In certain embodiments, atleast one instance of R^(A5) is —OC(═O)R^(a), —OC(═O)OR^(a), or—OC(═O)N(R^(a))₂.

In certain embodiments, m is 0. In certain embodiments, m is 1. Incertain embodiments, m is 2.

Formula (I) includes substituent R^(A6) on a nitrogen atom attached toRing A3. In certain embodiments, R^(A6) is H. In certain embodiments,R^(A6) is substituted or unsubstituted C₁₋₆ alkyl (e.g., —CH₃, Bn, —CF₃,unsubstituted ethyl, perfluoroethyl, unsubstituted propyl,perfluoropropyl, unsubstituted butyl, or perfluorobutyl). In certainembodiments, R^(A6) is a nitrogen protecting group (e.g., Bn, Boc, Cbz,Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

Formula (I) includes substituent R^(A7) on a nitrogen atom attached toRing A3. In certain embodiments, R^(A7) is H. In certain embodiments,R^(A7) is substituted or unsubstituted alkyl (e.g., substituted orunsubstituted C₁₋₆ alkyl). In certain embodiments, R^(A7) is —CH₃. Incertain embodiments, R^(A7) is —CF₃, Bn, unsubstituted ethyl,perfluoroethyl, unsubstituted propyl, perfluoropropyl, unsubstitutedbutyl, or perfluorobutyl. In certain embodiments, R^(A7) is substitutedor unsubstituted alkenyl (e.g., substituted or unsubstituted C₂₋₆alkenyl). In certain embodiments, R^(A7) is substituted or unsubstitutedalkynyl (e.g., substituted or unsubstituted C₁₋₆ alkynyl). In certainembodiments, R^(A7) is substituted or unsubstituted carbocyclyl (e.g.,substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclylcomprising zero, one, or two double bonds in the carbocyclic ringsystem). In certain embodiments, R^(A7) is substituted or unsubstitutedheterocyclyl (e.g., substituted or unsubstituted, 3- to 9-membered,monocyclic heterocyclyl comprising zero, one, or two double bonds in theheterocyclic ring system, wherein one, two, or three atoms in theheterocyclic ring system are independently nitrogen, oxygen, or sulfur).In certain embodiments, R^(A7) is substituted or unsubstitutedheteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered,monocyclic heteroaryl, wherein one, two, three, or four atoms in theheteroaryl ring system are independently nitrogen, oxygen, or sulfur).In certain embodiments, R^(A7) is —C(═O)R^(a) (e.g., —C(═O)(substitutedor unsubstituted alkyl) or —C(═O)(substituted or unsubstituted phenyl)),—C(═O)OR^(a) (e.g., —C(═O)O(substituted or unsubstituted alkyl) or—C(═O)O(substituted or unsubstituted phenyl)), or —C(═O)N(R^(a))₂ (e.g.,—C(═O)NH₂, —C(═O)NH(substituted or unsubstituted alkyl),—C(═O)NH(substituted or unsubstituted phenyl), —C(═O)N(substituted orunsubstituted alkyl)-(substituted or unsubstituted alkyl), or—C(═O)N(substituted or unsubstituted phenyl)-(substituted orunsubstituted alkyl)). In certain embodiments, R^(A7) is a nitrogenprotecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl,triphenylmethyl, acetyl, or Ts). In certain embodiments, R^(A7) is ofthe formula:

wherein:

each instance of R^(A8) is independently hydrogen, halogen, orsubstituted or unsubstituted C₁₋₆ alkyl;

u is 0, 1, 2, 3, or 4;

v is 1, 2, or 3;

w is 1, 2, or 3;

each instance of R^(A9) is independently halogen, or substituted orunsubstituted C₁₋₆ alkyl;

n is an integer between 0 and 13, inclusive; and

R^(A10) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted carbocyclyl, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)N(R^(a))₂, a nitrogen protecting group, or of anyone of Formulae (ii-1) to (ii-42):

wherein:

L³ is a bond or an optionally substituted CA hydrocarbon chain,optionally wherein one or more carbon units of the hydrocarbon chain areindependently replaced with —O—, —S—, —NR^(L3a)—, —NR^(L3a)C(═O)—,—C(═O)NR^(L3a)—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—,—NR^(L3a)C(═S)—, —C(═S)NR^(L3a)—, trans-CR^(L3b)═CR^(L3b)—,cis-CR^(L3b)═CR^(L3b)—, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—,—S(═O)NR^(L3a)—, —NR^(L3a)S(═O)—, —S(═O)₂—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR^(L3a)—, or —NR^(L3a)S(═O)₂—, wherein R^(L3a) is hydrogen,substituted or unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group,and wherein each occurrence of R^(L3b) is independently selected fromthe group consisting of hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, ortwo R^(L3b) groups are joined to form an optionally substitutedcarbocyclic or optionally substituted heterocyclic ring;

L⁴ is a bond or an optionally substituted C₁₋₄ hydrocarbon chain;

R^(E1) is selected from the group consisting of hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —CN, —CH₂OR^(E1a), —CH₂N(R^(E1a))₂,—CH₂SR^(E1a), —OR^(E1a), —N(R^(E1a))₂, —Si(R^(E1a))₃, and —SR^(E1a),wherein each occurrence of R^(E1a) is independently selected from thegroup consisting of hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or two R^(E1a)groups are joined to form an optionally substituted heterocyclic ring;

R^(E2) is selected from the group consisting of hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —CN, —CH₂OR^(E2a), —CH₂N(R^(E2a))₂,—CH₂SR^(E2a), —OR^(E2a), —N(R^(E2a))₂, and —SR^(E2a), wherein eachoccurrence of R^(E2a) is independently selected from the groupconsisting of hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or two R^(E2a)groups are joined to form an optionally substituted heterocyclic ring;

R^(E3) is selected from the group consisting of hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —CN, —CH₂OR^(E3a), —CH₂N(R^(E3a))₂,—CH₂SR^(E3a), —OR^(E3a), —N(R^(E3a))₂, and —SR^(E3a), wherein eachoccurrence of R^(E3a) is independently selected from the groupconsisting of hydrogen, optionally substituted alkyl, optionallysubstituted alkoxy, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or two R^(E3a) groups are joined to form anoptionally substituted heterocyclic ring; or R^(E1) and R^(E3), orR^(E2) and R^(E3), or R^(E1) and R^(E2) are joined to form an optionallysubstituted carbocyclic or optionally substituted heterocyclic ring;

R^(E4) is a leaving group;

R^(E5) is halogen;

Y is O, S, or NR^(E6), wherein R^(E6) is hydrogen, substituted orunsubstituted C₁₋₆ alkyl, or a nitrogen protecting group;

a is 1 or 2; and

each instance of z is independently 0, 1, 2, 3, 4, 5, or 6.

In certain embodiments, R^(A7) is of the formula:

In certain embodiments, R^(A7) is of the formula:

In certain embodiments, R^(A7) is of the formula:

wherein R^(a) is substituted or unsubstituted C₂₋₆ alkenyl. In certainembodiments, R^(A7) is of the formula:

wherein R^(a) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(A7) is of the formula:

In certain embodiments, R^(A7) is of the formula:

In certain embodiments, R^(A7) is of the formula:

In certain embodiments, R^(A7) is of the formula:

In certain embodiments, R^(A7) is of the formula:

Wherein R^(a) is substituted or unsubstituted C₂₋₆ alkenyl. In certainembodiments, R^(A7) is of the formula:

wherein R^(a) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(A7) is of the formula:

In certain embodiments, R^(A7) is of the formula:

In certain embodiments, all instances of R^(A8) are the same. In certainembodiments, two instances of R^(A8) are different from each other. Incertain embodiments, at least one instance of R^(A8) is H. In certainembodiments, each instance of R^(A8) is H. In certain embodiments, atleast one instance of R^(A8) is halogen (e.g., F, Cl, Br, or I). Incertain embodiments, at least one instance of R^(A8) is substituted orunsubstituted alkyl (e.g., substituted or unsubstituted C₁₋₆ alkyl). Incertain embodiments, at least one instance of R^(A8) is —CH₃. In certainembodiments, at least one instance of R^(A8) is —CF₃, Bn, unsubstitutedethyl, perfluoroethyl, unsubstituted propyl, perfluoropropyl,unsubstituted butyl, or perfluorobutyl.

In certain embodiments, u is 0. In certain embodiments, u is 1. Incertain embodiments, u is 2. In certain embodiments, u is 3. In certainembodiments, u is 4.

In certain embodiments, v is 1. In certain embodiments, v is 2. Incertain embodiments, v is 3. In certain embodiments, v is 4.

In certain embodiments, w is 1. In certain embodiments, w is 2. Incertain embodiments, w is 3.

In certain embodiments, v is 2; and w is 1. In certain embodiments, v is3; and w is 1. In certain embodiments, v is 4; and w is 1.

In certain embodiments, all instances of R^(A9) are the same. In certainembodiments, two instances of R^(A9) are different from each other. Incertain embodiments, at least one instance of R^(A9) is halogen (e.g.,F, Cl, Br, or I). In certain embodiments, at least one instance ofR^(A9) is substituted or unsubstituted alkyl (e.g., substituted orunsubstituted C₁₋₆ alkyl). In certain embodiments, at least one instanceof R^(A9) is —CH₃. In certain embodiments, at least one instance ofR^(A9) is —CF₃, Bn, unsubstituted ethyl, perfluoroethyl, unsubstitutedpropyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl.

In certain embodiments, n is 0. In certain embodiments, n is 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, or 13.

In certain embodiments, R^(A)10 is hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedcarbocyclyl, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, a nitrogenprotecting group, or of any one of Formulae (ii-1) to (ii-23). Incertain embodiments, R^(A)10 is H. In certain embodiments, R^(A)10 issubstituted or unsubstituted C₁₋₆ alkyl (e.g., C₁₋₆ alkyl substitutedwith one or more substituents independently selected from the groupconsisting of oxo; halogen; substituted or unsubstituted C₂₋₆ alkenyl;substituted or unsubstituted cyclopropyl; substituted or unsubstituted,4- to 7-membered monocyclic carbocyclyl comprising 1 or 2 double bondsin the carbocyclic ring system; substituted or unsubstituted oxiranyl;substituted or unsubstituted, 5- to 10-membered, monocyclic or bicyclicheteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring systemare independently oxygen, nitrogen, or sulfur; —CN; —(C═O)R^(a);—N(R^(a))(C═O)R^(a); —O(C═O)R^(a); —OR^(a); and —N(R^(a))₂). In certainembodiments, R^(A10) is substituted or unsubstituted C₂₋₆ alkenyl (e.g.,substituted or unsubstituted vinyl). In certain embodiments, R^(A10) issubstituted or unsubstituted C₂₋₆ alkynyl (e.g., substituted orunsubstituted ethynyl). In certain embodiments, R^(A10) is substitutedor unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to7-membered, monocyclic carbocyclyl comprising zero, one, or two doublebonds in the carbocyclic ring system). In certain embodiments, R^(A10)is —C(═O)R^(a). In certain embodiments, R^(A10) is —C(═O)(substituted orunsubstituted alkyl) (e.g., —C(═O)(substituted or unsubstituted C₁₋₆alkyl), such as —C(═O)Et). In certain embodiments, R^(A10) is—C(═O)(substituted or unsubstituted alkenyl) (e.g., —C(═O)(substitutedor unsubstituted C₂₋₆ alkenyl), such as —C(═O)—CH═CH₂). In certainembodiments, R^(A10) is —C(═O)(substituted or unsubstitutedcarbocyclyl). In certain embodiments, R^(A10) is —C(═O)(substituted orunsubstituted heterocyclyl). In certain embodiments, R^(A10) is—C(═O)(substituted or unsubstituted phenyl). In certain embodiments,R^(A10) is —C(═O)(substituted or unsubstituted heteroaryl). In certainembodiments, R^(A10) is —C(═O)OR^(a) (e.g., —C(═O)O(substituted orunsubstituted alkyl) or —C(═O)O(substituted or unsubstituted phenyl)) or—C(═O)N(R^(a))₂ (e.g., —C(═O)NH₂, —C(═O)NH(substituted or unsubstitutedalkyl), —C(═O)NH(substituted or unsubstituted phenyl),—C(═O)N(substituted or unsubstituted alkyl)-(substituted orunsubstituted alkyl), or —C(═O)N(substituted or unsubstitutedphenyl)-(substituted or unsubstituted alkyl)). In certain embodiments,R^(A10) is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc,trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certainembodiments, R^(A10) is of any one of Formulae (ii-1) to (ii-23). Incertain embodiments, R^(A10) is of any one of Formulae (ii-24) to(ii-42). In certain embodiments, R^(A10) is of Formula (ii-1) (e.g., ofthe formula:

In certain embodiments, R^(A10) is of Formula (ii-3) (e.g., of theformula:

In certain embodiments, R^(A10) is of any one of the formulae shown inTable 1A.

TABLE 1A Exemplary moieties.

In certain embodiments, L³ is a bond. In certain embodiments, L³ is anoptionally substituted C₁₋₄ hydrocarbon chain. In certain embodiments,L³ is an optionally substituted C₁₋₄ hydrocarbon chain, wherein one ormore carbon units of the hydrocarbon chain are independently replacedwith —O—, —S—, —NR^(L3a)—, —NR^(L3a)C(═O)—, —C(═O)NR^(L3a)—, —SC(═O)—,—C(═O)S—, —OC(═O)—, —C(═O)O—, —NR^(L3a)C(═S)—, —C(═S)NR^(L3a)—,trans-CR^(L3b)═CR^(L3b)—, cis-CR^(L3b)═CR^(L3b)—, —C≡C—, —S(═O)—,—S(═O)O—, —OS(═O)—, —S(═O)NR^(L3a)—, —NR^(L3a)S(═O)—, —S(═O)₂—,—S(═O)₂O—, —OS(═O)₂—, —S(═O)₂NR^(L3a)—, or —NR^(L3a)S(═O)₂—. In certainembodiments, L³ is an optionally substituted C₁₋₄ hydrocarbon chain,wherein one carbon unit of the hydrocarbon chain is replaced with—NR^(L3a)— (e.g., —NH—). In certain embodiments, L³ is of the formula:—(CH₂)₁₋₄—NR^(L3a)— (e.g., —(CH₂)₁₋₄—NH—) or —NR^(L3a)—CH₂)₁₋₄— (e.g.,—NH—CH₂)₁₋₄—).

In certain embodiments, R^(L3a) is hydrogen.

In certain embodiments, at least one instance of R^(L3b) is hydrogen. Incertain embodiments, each instance of R^(L3b) is hydrogen. In certainembodiments, at least one instance of R^(L3b) is halogen (e.g., F orCl). In certain embodiments, each instance of R^(L3b) is halogen (e.g.,F or Cl). In certain embodiments, at least one instance of R^(L3b) isoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl. In certain embodiments, two R^(L3b) groups arejoined to form an optionally substituted carbocyclic or optionallysubstituted heterocyclic ring.

In certain embodiments, L⁴ is a bond. In certain embodiments, L⁴ is anoptionally substituted C₁₋₄ hydrocarbon chain.

In certain embodiments, R^(E1) is hydrogen. In certain embodiments,R^(E1) is halogen. In certain embodiments, R^(E1) is optionallysubstituted alkyl (e.g., substituted or unsubstituted C₁₋₆ alkyl). Incertain embodiments, R^(E1) is optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, —CN, —CH₂OR^(E1a), —CH₂N(R^(E1a))₂,—CH₂SR^(E1a), —OR^(E1a), —N(R^(E1a))₂, —Si(R^(E1a))₃, or —SR^(E1a).

In certain embodiments, R^(E2) is hydrogen. In certain embodiments,R^(E2) is halogen. In certain embodiments, R^(E2) is optionallysubstituted alkyl (e.g., substituted or unsubstituted C₁₋₆ alkyl). Incertain embodiments, R^(E2) is optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, —CN, —CH₂OR^(E2a), —CH₂N(R^(E2a))₂,—CH₂SR^(E2a), —OR^(E2a), —N(R^(E2a))₂, or —SR^(E2a).

In certain embodiments, R^(E3) is hydrogen. In certain embodiments,R^(E3) is halogen. In certain embodiments, R^(E3) is optionallysubstituted alkyl (e.g., substituted or unsubstituted C₁₋₆ alkyl). Incertain embodiments, R^(E3) is optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, —CN, —CH₂OR^(E3a), —CH₂N(R^(E3a))₂,—CH₂SR^(E3a), —OR^(E3a), —N(R^(E3a))₂, or —SR^(E3a).

In certain embodiments, R^(E1) and R^(E3) are joined to form anoptionally substituted carbocyclic ring. In certain embodiments, R^(E1)and R^(E3) are joined to form an optionally substituted heterocyclicring. In certain embodiments, R^(E2) and R^(E3) are joined to form anoptionally substituted carbocyclic ring. In certain embodiments, R^(E2)and R^(E3) are joined to form an optionally substituted heterocyclicring. In certain embodiments, R^(E1) and R^(E2) are joined to form anoptionally substituted carbocyclic ring. In certain embodiments, R^(E1)and R^(E2) are joined to form an optionally substituted heterocyclicring.

In certain embodiments, R^(E4) is halogen (e.g., F, Cl, Br, or I). Incertain embodiments, R^(E4) is —OS(═O)R^(E4a) or —OS(═O)₂R^(E4a),wherein R^(E4a) is substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In certain embodiments, R^(E4) is —OMs, —OTf, —OTs, —OBs, or2-nitrobenzenesulfonyloxy. In certain embodiments, R^(E4) is —OR^(E4a).In certain embodiments, R^(E4) is —OMe, —OCF₃, or —OPh. In certainembodiments, R^(E4) is —OC(═O)R^(E4a). In certain embodiments, R^(E4) is—OC(═O)Me, —OC(═O)CF₃, —OC(═O)Ph, or —OC(═O)Cl. In certain embodiments,R^(E4) is —OC(═O)OR^(E4a). In certain embodiments, R^(E4) is —OC(═O)OMeor —OC(═O)O(t-Bu).

In certain embodiments, R^(E5) is F, Cl, Br, or I.

In certain embodiments, Y is O. In certain embodiments, Y is S. Incertain embodiments, Y is NR^(E6) (e.g., NH).

In certain embodiments, R^(E6) is H.

In certain embodiments, a is 1. In certain embodiments, a is 2.

In certain embodiments, at least one instance of z is 0. In certainembodiments, at least one instance of z is 1. In certain embodiments, atleast one instance of z is 2, 3, 4, 5, or 6. In certain embodiments, twoinstacnes of z are the same. In certain embodiments, two instacnes of zare different from each other.

In certain embodiments, a compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof, wherein R^(a) is substituted or unsubstituted C₁₋₆alkyl or substituted or unsubstituted C₂₋₆ alkenyl.

In certain embodiments, a compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof, wherein R^(a) is substituted or unsubstituted C₁₋₆alkyl or substituted or unsubstituted C₂₋₆ alkenyl.

Exemplary compounds of Formula (I) include, but are not limited to:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopic ally labeledderivatives, and prodrugs thereof.

Compounds of Formula (II)

In certain embodiments, a compound described herein is of Formula (II):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof, wherein:

each instance of R^(B1) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(b), —N(R^(b))₂,—SR^(b), —CN, —SCN, —C(═NR^(b))R^(b), —C(═NR^(b))OR^(b),—C(═NR^(b))N(R^(b))₂, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)N(R^(b))₂, —NO₂,—NR^(b)C(═O)R^(b), —NR^(b)C(═O)OR^(b), —NR^(b)C(═O)N(R^(b))₂,—OC(═O)R^(b), —OC(═O)OR^(b), or —OC(═O)N(R^(b))₂;

each instance of R^(b) is independently hydrogen, substituted orunsubstituted acyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two instancesof R^(b) are joined to form a substituted or unsubstituted, heterocyclicring, or substituted or unsubstituted, heteroaryl ring;

p is 0, 1, 2, 3, 4, or 5;

L^(B) is —C(═O)—NR^(B2)— or —NR^(B2)—C(═O)—, wherein R^(B2) is hydrogen,substituted or unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group;

R^(B3) is hydrogen, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —OR^(b), —N(R^(b))₂, —SR^(b),—CN, —SCN, —C(═NR^(b))R^(b), —C(═NR^(b))OR^(b), —C(═NR^(b))N(R^(b))₂,—C(═O)R^(b), —C(═O)OR^(b), —C(═O)N(R^(b))₂, —NO₂, —NR^(b)C(═O)R^(b),—NR^(b)C(═O)OR^(b), —NR^(b)C(═O)N(R^(b))₂, —OC(═O)R^(b), —OC(═O)OR^(b),or —OC(═O)N(R^(b))₂;

R^(B4) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group;

Ring B3 is a substituted or unsubstituted pyrazolyl ring;

each instance of R^(B5) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(b), —N(R^(b))₂,—SR^(b), —CN, —SCN, —C(═NR^(b))R^(b), —C(═NR^(b))OR^(b),—C(═NR^(b))N(R^(b))₂, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)N(R^(b))₂, —NO₂,—NR^(b)C(═O)R^(b), —NR^(b)C(═O)OR^(b), —NR^(b)C(═O)N(R^(b))₂,—OC(═O)R^(b), —OC(═O)OR^(b), or —OC(═O)N(R^(b))₂;

q is 0, 1, or 2;

R^(B6) is substituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl,—C(═O)R^(b), —C(═O)OR^(b), or —C(═O)N(R^(b))₂.

Formula (II) includes as Ring B1 a phenyl ring that is unsubstituted(e.g., when p is 0) or substituted (e.g., when p is 1, 2, 3, 4, or 5)with one or more substituents R^(B1). In certain embodiments, Ring B1 isof the formula:

In certain embodiments, Ring B1 is of the formula:

In certain embodiments, Ring B1 is of the formula:

wherein each instance of R^(B1) is independently substituted orunsubstituted alkyl (e.g., substituted or unsubstituted C₁₋₆ alkyl, suchas —CH₃, —CF₃, Bn, unsubstituted ethyl, perfluoroethyl, unsubstitutedpropyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl) orhalogen (e.g., F, Cl, Br, or I). In certain embodiments, Ring B1 is ofthe formula:

In certain embodiments, Ring B1 is of the formula:

In Formula (II), Ring B1 may include one or more substituents R^(B1). Incertain embodiments, all instances of R^(B1) are the same. In certainembodiments, two instances of R^(B1) are different from each other. Incertain embodiments, at least one instance of R^(B1) is halogen (e.g.,F, Cl, Br, or I). In certain embodiments, at least one instance ofR^(B1) is substituted or unsubstituted alkyl (e.g., substituted orunsubstituted C₁₋₆ alkyl). In certain embodiments, at least one instanceof R^(B1) is —CH₃. In certain embodiments, at least one instance ofR^(B1) is —CF₃, Bn, unsubstituted ethyl, perfluoroethyl, unsubstitutedpropyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl. Incertain embodiments, at least one instance of R^(B1) is substituted orunsubstituted alkenyl (e.g., substituted or unsubstituted C₂₋₆ alkenyl).In certain embodiments, at least one instance of R^(B1) is substitutedor unsubstituted alkynyl (e.g., substituted or unsubstituted C₁₋₆alkynyl). In certain embodiments, at least one instance of R^(B1) issubstituted or unsubstituted carbocyclyl (e.g., substituted orunsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero,one, or two double bonds in the carbocyclic ring system). In certainembodiments, at least one instance of R^(B1) is substituted orunsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to9-membered, monocyclic heterocyclyl comprising zero, one, or two doublebonds in the heterocyclic ring system, wherein one, two, or three atomsin the heterocyclic ring system are independently nitrogen, oxygen, orsulfur). In certain embodiments, at least one instance of R^(B1) issubstituted or unsubstituted aryl (e.g., substituted or unsubstituted,6- to 10-membered aryl). In certain embodiments, at least one instanceof R^(B1) is substituted or unsubstituted phenyl. In certainembodiments, at least one instance of R^(B1) is substituted orunsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to6-membered, monocyclic heteroaryl, wherein one, two, three, or fouratoms in the heteroaryl ring system are independently nitrogen, oxygen,or sulfur). In certain embodiments, at least one instance of R^(B1) is—OR^(b) (e.g., —OH, —O(substituted or unsubstituted C₁₋₆ alkyl) (e.g.,—OMe, —OEt, —OPr, —OBu, or —OBn), or —O(substituted or unsubstitutedphenyl) (e.g., —OPh)). In certain embodiments, at least one instance ofR^(B1) is —SR^(b) (e.g., —SH, —S(substituted or unsubstituted C₁₋₆alkyl) (e.g., —SMe, —SEt, —SPr, —SBu, or —SBn), or —S(substituted orunsubstituted phenyl) (e.g., —SPh)). In certain embodiments, at leastone instance of R^(B1) is —N(R^(b))₂ (e.g., —NH₂, —NH(substituted orunsubstituted C₁₋₆ alkyl) (e.g., —NHMe), or —N(substituted orunsubstituted C₁₋₆ alkyl)-(substituted or unsubstituted C₁₋₆ alkyl)(e.g., —NMe₂)). In certain embodiments, at least one instance of R^(B1)is —CN, —SCN, or —NO₂. In certain embodiments, at least one instance ofR^(B1) is —C(═NR^(b))R^(b), —C(═NR^(b))OR^(b), or —C(═NR^(b))N(R^(b))₂.In certain embodiments, at least one instance of R^(B1) is —C(═O)R^(b)(e.g., —C(═O)(substituted or unsubstituted alkyl) or —C(═O)(substitutedor unsubstituted phenyl)), —C(═O)OR^(b) (e.g., —C(═O)O(substituted orunsubstituted alkyl) or —C(═O)O(substituted or unsubstituted phenyl)),or —C(═O)N(R^(b))₂ (e.g., —C(═O)NH₂, —C(═O)NH(substituted orunsubstituted alkyl), —C(═O)NH(substituted or unsubstituted phenyl),—C(═O)N(substituted or unsubstituted alkyl)-(substituted orunsubstituted alkyl), or —C(═O)N(substituted or unsubstitutedphenyl)-(substituted or unsubstituted alkyl)). In certain embodiments,at least one instance of R^(B1) is —NR^(b)C(═O)R^(b),—NR^(b)C(═O)OR^(b), or —NR^(b)C(═O)N(R^(b))₂. In certain embodiments, atleast one instance of R^(B1) is —OC(═O)R^(b), —OC(═O)OR^(b), or—OC(═O)N(R^(b))₂.

When Formula (II) includes two or more instances of substituent R^(b),any two instances of R^(b) may be the same or different from each other.In certain embodiments, at least one instance of R^(b) is H. In certainembodiments, each instance of R^(b) is H. In certain embodiments, atleast one instance of R^(b) is substituted or unsubstituted acyl (e.g.,acetyl). In certain embodiments, at least one instance of R^(b) issubstituted or unsubstituted alkyl (e.g., substituted or unsubstitutedC₁₋₆ alkyl). In certain embodiments, at least one instance of R^(b) is—CH₃. In certain embodiments, at least one instance of R^(b) is —CF₃,Bn, unsubstituted ethyl, perfluoroethyl, unsubstituted propyl,perfluoropropyl, unsubstituted butyl, or perfluorobutyl. In certainembodiments, at least one instance of R^(b) is substituted orunsubstituted alkenyl (e.g., substituted or unsubstituted C₂₋₆ alkenyl).In certain embodiments, at least one instance of R^(b) is substituted orunsubstituted alkynyl (e.g., substituted or unsubstituted C₁₋₆ alkynyl).In certain embodiments, at least one instance of R^(b) is substituted orunsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to7-membered, monocyclic carbocyclyl comprising zero, one, or two doublebonds in the carbocyclic ring system). In certain embodiments, at leastone instance of R^(b) is substituted or unsubstituted heterocyclyl(e.g., substituted or unsubstituted, 3- to 9-membered, monocyclicheterocyclyl comprising zero, one, or two double bonds in theheterocyclic ring system, wherein one, two, or three atoms in theheterocyclic ring system are independently nitrogen, oxygen, or sulfur).In certain embodiments, at least one instance of R^(b) is substituted orunsubstituted aryl (e.g., substituted or unsubstituted, 6- to10-membered aryl). In certain embodiments, at least one instance ofR^(b) is substituted or unsubstituted phenyl. In certain embodiments, atleast one instance of R^(b) is substituted or unsubstituted heteroaryl(e.g., substituted or unsubstituted, 5- to 6-membered, monocyclicheteroaryl, wherein one, two, three, or four atoms in the heteroarylring system are independently nitrogen, oxygen, or sulfur). In certainembodiments, at least one instance of R^(b) is a nitrogen protectinggroup (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl,acetyl, or Ts) when attached to a nitrogen atom. In certain embodiments,R^(b) is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS,TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) whenattached to an oxygen atom. In certain embodiments, R^(b) is a sulfurprotecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to asulfur atom. In certain embodiments, two instances of R^(b) are joinedto form a substituted or unsubstituted, heterocyclic ring (e.g.,substituted or unsubstituted, 5- to 6-membered, monocyclic heterocyclicring comprising zero, one, or two double bonds in the heterocyclic ringsystem, wherein one, two, or three atoms in the heterocyclic ring systemare independently nitrogen, oxygen, or sulfur). In certain embodiments,two instances of R^(b) are joined to form a substituted or unsubstitutedheteroaryl ring (e.g., substituted or unsubstituted, 5- to 6-membered,monocyclic heteroaryl ring, wherein one, two, three, or four atoms inthe heteroaryl ring system are independently nitrogen, oxygen, orsulfur).

In certain embodiments, p is 0. In certain embodiments, p is 1. Incertain embodiments, p is 2. In certain embodiments, p is 3. In certainembodiments, p is 4. In certain embodiments, p is 5.

In certain embodiments, p is 1; and R^(B1) is substituted orunsubstituted alkyl (e.g., substituted or unsubstituted C₁₋₆ alkyl, suchas —CH₃, —CF₃, Bn, unsubstituted ethyl, perfluoroethyl, unsubstitutedpropyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl) orhalogen (e.g., F, Cl, Br, or I). In certain embodiments, p is 2; andeach of the two instances of R^(B1) is independently substituted orunsubstituted alkyl (e.g., substituted or unsubstituted C₁₋₆ alkyl, suchas —CH₃, —CF₃, Bn, unsubstituted ethyl, perfluoroethyl, unsubstitutedpropyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl) orhalogen (e.g., F, Cl, Br, or I).

Formula (II) includes divalent linker L^(B) connecting Ring B1 to thethiazolyl ring. In certain embodiments, L^(B) is —C(═O)—N(R^(B2))—(e.g., —C(═O)—NH—). In certain embodiments, L^(B) is —N(R^(B2))—C(═O)—(e.g., —NH—C(═O)—).

In certain embodiments, R^(B2) is H. In certain embodiments, R^(B2) issubstituted or unsubstituted C₁₋₆ alkyl (e.g., —CH₃, Bn, —CF₃,unsubstituted ethyl, perfluoroethyl, unsubstituted propyl,perfluoropropyl, unsubstituted butyl, or perfluorobutyl). In certainembodiments, R^(B2) is a nitrogen protecting group (e.g., Bn, Boc, Cbz,Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

The thiazolyl ring of Formula (II) includes substituent R^(B3). Incertain embodiments, R^(B3) is H. In certain embodiments, R^(B3) ishalogen (e.g., F, Cl, Br, or I). In certain embodiments, R^(B3) issubstituted or unsubstituted alkyl (e.g., substituted or unsubstitutedC₁₋₆ alkyl). In certain embodiments, R^(B3) is —CH₃. In certainembodiments, R^(B3) is —CF₃, Bn, unsubstituted ethyl, perfluoroethyl,unsubstituted propyl, perfluoropropyl, unsubstituted butyl, orperfluorobutyl. In certain embodiments, R^(B3) is substituted orunsubstituted alkenyl (e.g., substituted or unsubstituted C₂₋₆ alkenyl).In certain embodiments, R^(B3) is substituted or unsubstituted alkynyl(e.g., substituted or unsubstituted C₁₋₆ alkynyl). In certainembodiments, R^(B3) is substituted or unsubstituted carbocyclyl (e.g.,substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclylcomprising zero, one, or two double bonds in the carbocyclic ringsystem). In certain embodiments, R^(B3) is substituted or unsubstitutedheterocyclyl (e.g., substituted or unsubstituted, 3- to 9-membered,monocyclic heterocyclyl comprising zero, one, or two double bonds in theheterocyclic ring system, wherein one, two, or three atoms in theheterocyclic ring system are independently nitrogen, oxygen, or sulfur).In certain embodiments, R^(B3) is substituted or unsubstituted aryl(e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certainembodiments, R^(B3) is substituted or unsubstituted phenyl. In certainembodiments, R^(B3) is substituted or unsubstituted heteroaryl (e.g.,substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl,wherein one, two, three, or four atoms in the heteroaryl ring system areindependently nitrogen, oxygen, or sulfur). In certain embodiments,R^(B3) is —OR^(b) (e.g., —OH, —O(substituted or unsubstituted C₁₋₆alkyl) (e.g., —OMe, —OEt, —OPr, —OBu, or —OBn), or —O(substituted orunsubstituted phenyl) (e.g., —OPh)). In certain embodiments, R^(B3) is—SR^(b)(e.g., —SH, —S(substituted or unsubstituted C₁₋₆ alkyl) (e.g.,—SMe, —SEt, —SPr, —SBu, or —SBn), or —S(substituted or unsubstitutedphenyl) (e.g., —SPh)). In certain embodiments, R^(B3) is —N(R^(b))₂(e.g., —NH₂, —NH(substituted or unsubstituted C₁₋₆ alkyl) (e.g., —NHMe),or —N(substituted or unsubstituted C₁₋₆ alkyl)-(substituted orunsubstituted C₁₋₆ alkyl) (e.g., —NMe₂)). In certain embodiments, R^(B3)is —CN, —SCN, or —NO₂. In certain embodiments, R^(B3) is—C(═NR^(b))R^(b), —C(═NR^(b))OR^(b), or —C(═NR^(b))N(R^(b))₂. In certainembodiments, R^(B3) is —C(═O)R^(b)(e.g., —C(═O)(substituted orunsubstituted alkyl) or —C(═O)(substituted or unsubstituted phenyl)),—C(═O)OR^(b) (e.g., —C(═O)O(substituted or unsubstituted alkyl) or—C(═O)O(substituted or unsubstituted phenyl)), or —C(═O)N(R^(b))₂ (e.g.,—C(═O)NH₂, —C(═O)NH(substituted or unsubstituted alkyl),—C(═O)NH(substituted or unsubstituted phenyl), —C(═O)N(substituted orunsubstituted alkyl)-(substituted or unsubstituted alkyl), or—C(═O)N(substituted or unsubstituted phenyl)-(substituted orunsubstituted alkyl)). In certain embodiments, R^(B3) is—NR^(b)C(═O)R^(b), —NR^(b)C(═O)OR^(b), or —NR^(b)C(═O)N(R^(b))₂. Incertain embodiments, R^(B3) is —OC(═O)R^(b), —OC(═O)OR^(b), or—OC(═O)N(R^(b))₂.

Formula (II) includes substituent R^(B4) on a nitrogen atom attached tothe thiazolyl ring. In certain embodiments, R^(B4) is H. In certainembodiments, R^(B4) is substituted or unsubstituted C₁₋₆ alkyl (e.g.,—CH₃, Bn, —CF₃, unsubstituted ethyl, perfluoroethyl, unsubstitutedpropyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl). Incertain embodiments, R^(B4) is a nitrogen protecting group (e.g., Bn,Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

Formula (II) includes as Ring B3 a pyrazolyl ring that is unsubstituted(e.g., when q is 0) or substituted (e.g., when q is 1 or 2) with one ormore substituents R^(B5). In certain embodiments, Ring B3 is of theformula:

wherein the nitrogen atom labeled with “1” is attached to R^(B6), andthe carbon atom labeled with “3” is attached to the nitrogen atom towhich R^(B4) is attached. In certain embodiments, Ring B3 is of theformula:

wherein the nitrogen atom labeled with “1” is attached to R^(B6), andthe carbon atom labeled with “4” is attached to the nitrogen atom towhich R^(B4) is attached.

In Formula (II), Ring B3 may include one or two substituents R^(B5). Incertain embodiments, two instances of R^(B5) are the same. In certainembodiments, two instances of R^(B5) are different from each other. Incertain embodiments, at least one instance of R^(B5) is halogen (e.g.,F, Cl, Br, or I). In certain embodiments, at least one instance ofR^(B5) is substituted or unsubstituted alkyl (e.g., substituted orunsubstituted C₁₋₆ alkyl). In certain embodiments, at least one instanceof R^(B5) is —CH₃. In certain embodiments, at least one instance ofR^(B5) is —CF₃, Bn, unsubstituted ethyl, perfluoroethyl, unsubstitutedpropyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl. Incertain embodiments, at least one instance of R^(B5) is substituted orunsubstituted alkenyl (e.g., substituted or unsubstituted C₂₋₆ alkenyl).In certain embodiments, at least one instance of R^(B5) is substitutedor unsubstituted alkynyl (e.g., substituted or unsubstituted C₁₋₆alkynyl). In certain embodiments, at least one instance of R^(B5) issubstituted or unsubstituted carbocyclyl (e.g., substituted orunsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero,one, or two double bonds in the carbocyclic ring system). In certainembodiments, at least one instance of R^(B5) is substituted orunsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to9-membered, monocyclic heterocyclyl comprising zero, one, or two doublebonds in the heterocyclic ring system, wherein one, two, or three atomsin the heterocyclic ring system are independently nitrogen, oxygen, orsulfur). In certain embodiments, at least one instance of R^(B5) issubstituted or unsubstituted aryl (e.g., substituted or unsubstituted,6- to 10-membered aryl). In certain embodiments, at least one instanceof R^(B5) is substituted or unsubstituted phenyl. In certainembodiments, at least one instance of R^(B5) is substituted orunsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to6-membered, monocyclic heteroaryl, wherein one, two, three, or fouratoms in the heteroaryl ring system are independently nitrogen, oxygen,or sulfur). In certain embodiments, at least one instance of R^(B5) is—OR^(b) (e.g., —OH, —O(substituted or unsubstituted C₁₋₆ alkyl) (e.g.,—OMe, —OEt, —OPr, —OBu, or —OBn), or —O(substituted or unsubstitutedphenyl) (e.g., —OPh)). In certain embodiments, at least one instance ofR^(B5) is —SR^(b) (e.g., —SH, —S(substituted or unsubstituted C₁₋₆alkyl) (e.g., —SMe, —SEt, —SPr, —SBu, or —SBn), or —S(substituted orunsubstituted phenyl) (e.g., —SPh)). In certain embodiments, at leastone instance of R^(B5) is —N(R^(b))₂ (e.g., —NH₂, —NH(substituted orunsubstituted C₁₋₆ alkyl) (e.g., —NHMe), or —N(substituted orunsubstituted C₁₋₆ alkyl)-(substituted or unsubstituted C₁₋₆ alkyl)(e.g., —NMe₂)). In certain embodiments, at least one instance of R^(B5)is —CN, —SCN, or —NO₂. In certain embodiments, at least one instance ofR^(B5) is —C(═NR^(b))R^(b), —C(═NR^(b))OR^(b), or —C(═NR^(b))N(R^(b))₂.In certain embodiments, at least one instance of R^(B5) is —C(═O)R^(b)(e.g., —C(═O)(substituted or unsubstituted alkyl) or —C(═O)(substitutedor unsubstituted phenyl)), —C(═O)OR^(b) (e.g., —C(═O)O(substituted orunsubstituted alkyl) or —C(═O)O(substituted or unsubstituted phenyl)),or —C(═O)N(R^(b))₂ (e.g., —C(═O)NH₂, —C(═O)NH(substituted orunsubstituted alkyl), —C(═O)NH(substituted or unsubstituted phenyl),—C(═O)N(substituted or unsubstituted alkyl)-(substituted orunsubstituted alkyl), or —C(═O)N(substituted or unsubstitutedphenyl)-(substituted or unsubstituted alkyl)). In certain embodiments,at least one instance of R^(B5) is —NR^(b)C(═O)R^(b),—NR^(b)C(═O)OR^(b), or —NR^(b)C(═O)N(R^(b))₂. In certain embodiments, atleast one instance of R^(B5) is —OC(═O)R^(b), —OC(═O)OR^(b), or—OC(═O)N(R^(b))₂.

In certain embodiments, q is 0. In certain embodiments, q is 1. Incertain embodiments, q is 2.

Formula (II) includes substituent R^(B6) on a nitrogen atom attached toRing B3. In certain embodiments, R^(B6) is substituted alkyl (e.g.,substituted C₁₋₆ alkyl). In certain embodiments, R^(B6) is —CF₃, Bn,perfluoroethyl, perfluoropropyl, or perfluorobutyl. In certainembodiments, R^(B6) is substituted or unsubstituted alkenyl (e.g.,substituted or unsubstituted C₂₋₆ alkenyl). In certain embodiments,R^(B6) is substituted or unsubstituted alkynyl (e.g., substituted orunsubstituted C₁₋₆ alkynyl). In certain embodiments, R^(B6) issubstituted or unsubstituted carbocyclyl (e.g., substituted orunsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero,one, or two double bonds in the carbocyclic ring system). In certainembodiments, R^(B6) is substituted or unsubstituted heterocyclyl (e.g.,substituted or unsubstituted, 3- to 9-membered, monocyclic heterocyclylcomprising zero, one, or two double bonds in the heterocyclic ringsystem, wherein one, two, or three atoms in the heterocyclic ring systemare independently nitrogen, oxygen, or sulfur). In certain embodiments,R^(B6) is substituted or unsubstituted aryl (e.g., substituted orunsubstituted, 6- to 10-membered aryl). In certain embodiments, R^(B6)is substituted or unsubstituted phenyl. In certain embodiments, R^(B6)is substituted or unsubstituted heteroaryl (e.g., substituted orunsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one,two, three, or four atoms in the heteroaryl ring system areindependently nitrogen, oxygen, or sulfur). In certain embodiments,R^(B6) is —C(═O)R^(b) (e.g., —C(═O)(substituted or unsubstituted alkyl)or —C(═O)(substituted or unsubstituted phenyl)), —C(═O)OR^(b) (e.g.,—C(═O)O(substituted or unsubstituted alkyl) or —C(═O)O(substituted orunsubstituted phenyl)), or —C(═O)N(R^(b))₂ (e.g., —C(═O)NH₂,—C(═O)NH(substituted or unsubstituted alkyl), —C(═O)NH(substituted orunsubstituted phenyl), —C(═O)N(substituted or unsubstitutedalkyl)-(substituted or unsubstituted alkyl), or —C(═O)N(substituted orunsubstituted phenyl)-(substituted or unsubstituted alkyl)). In certainembodiments, R^(B6) is of the formula:

wherein:

each instance of R^(B7) is independently hydrogen, halogen, orsubstituted or unsubstituted C₁₋₆ alkyl;

x is 0, 1, 2, 3, or 4;

y is 1, 2, 3, or 4;

h is 1, 2, or 3;

each instance of R^(B8) is independently halogen, or substituted orunsubstituted C₁₋₆ alkyl;

g is an integer between 0 and 13, inclusive; and

R^(B9) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, substitutedor unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstituted carbocyclyl, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)N(R^(a))₂, a nitrogen protecting group, or of anyone of Formulae (ii-1) to (ii-42):

wherein:

L³ is a bond or an optionally substituted C₁₋₄ hydrocarbon chain,optionally wherein one or more carbon units of the hydrocarbon chain areindependently replaced with —O—, —S—, —NR^(L3a)—, —NR^(L3a)C(═O)—,—C(═O)NR^(L3a)—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—,—NR^(L3a)C(═S)—, —C(═S)NR^(L3a)—, trans-CR^(L3b)═CR^(L3b)—,cis-CR^(L3b)═CR^(L3b)—, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—,—S(═O)NR^(L3a)—, —NR^(L3a)S(═O)—, —S(═O)₂—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR^(L3a)—, or —NR^(L3a)S(═O)₂—, wherein R^(L3a) is hydrogen,substituted or unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group,and wherein each occurrence of R^(L3b) is independently selected fromthe group consisting of hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, ortwo R^(L3b) groups are joined to form an optionally substitutedcarbocyclic or optionally substituted heterocyclic ring;

L⁴ is a bond or an optionally substituted C₁₋₄ hydrocarbon chain;

R^(E1) is selected from the group consisting of hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —CN, —CH₂OR^(E1a), —CH₂N(R^(E1a))₂,—CH₂SR^(E1a), —OR^(E1a), —N(R^(E1a))₂, —Si(R^(E1a))₃, and —SR^(E1a),wherein each occurrence of R^(E1a) is independently selected from thegroup consisting of hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or two R^(E1a)groups are joined to form an optionally substituted heterocyclic ring;

R^(E2) is selected from the group consisting of hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —CN, —CH₂OR^(E2a), —CH₂N(R^(E2a))₂,—CH₂SR^(E2a), —OR^(E2a), —N(R^(E2a))₂, and —SR^(E2a), wherein eachoccurrence of R^(E2a) is independently selected from the groupconsisting of hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or two R^(E2a)groups are joined to form an optionally substituted heterocyclic ring;

R^(E3) is selected from the group consisting of hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —CN, —CH₂OR^(E3a), —CH₂N(R^(E3a))₂,—CH₂SR^(E3a), —OR^(E3a), —N(R^(E3a))₂, and —SR^(E3a), wherein eachoccurrence of R^(E3a) is independently selected from the groupconsisting of hydrogen, optionally substituted alkyl, optionallysubstituted alkoxy, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or two R^(E3a) groups are joined to form anoptionally substituted heterocyclic ring; or R^(E1) and R^(E3), orR^(E2) and R^(E3), or R^(E1) and R^(E2) are joined to form an optionallysubstituted carbocyclic or optionally substituted heterocyclic ring;

R^(E4) is a leaving group;

R^(E5) is halogen;

Y is O, S, or NR^(E6), wherein R^(E6) is hydrogen, substituted orunsubstituted C₁₋₆ alkyl, or a nitrogen protecting group;

a is 1 or 2; and

each instance of z is independently 0, 1, 2, 3, 4, 5, or 6.

In certain embodiments, R^(B6) is of the formula:

In certain embodiments, R^(B6) is of the formula:

In certain embodiments, R^(B6) is of the formula:

wherein R^(b) is substituted or unsubstituted C₂₋₆ alkenyl. In certainembodiments, R^(B6) is of the formula:

wherein R^(b) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(B6) is of the formula:

In certain embodiments, R^(B6) is of the formula:

In certain embodiments, R^(B6) is of the formula:

In certain embodiments, R^(B6) is of the formula:

In certain embodiments, R^(B6) is of the formula:

wherein R^(b) is substituted or unsubstituted C₂₋₆ alkenyl. In certainembodiments, R^(B6) is of the formula:

wherein R^(b) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(B6) is of the formula:

In certain embodiments, R^(B6) is of the formula:

In certain embodiments, all instances of R^(B7) are the same. In certainembodiments, two instances of R^(B7) are different from each other. Incertain embodiments, at least one instance of R^(B7) is H. In certainembodiments, each instance of R^(B7) is H. In certain embodiments, atleast one instance of R^(B7) is halogen (e.g., F, Cl, Br, or I). Incertain embodiments, at least one instance of R^(B7) is substituted orunsubstituted alkyl (e.g., substituted or unsubstituted C₁₋₆ alkyl). Incertain embodiments, at least one instance of R^(B7) is —CH₃. In certainembodiments, at least one instance of R^(B7) is —CF₃, Bn, unsubstitutedethyl, perfluoroethyl, unsubstituted propyl, perfluoropropyl,unsubstituted butyl, or perfluorobutyl.

In certain embodiments, x is 0. In certain embodiments, x is 1. Incertain embodiments, x is 2. In certain embodiments, x is 3. In certainembodiments, x is 4.

In certain embodiments, y is 1. In certain embodiments, y is 2. Incertain embodiments, y is 3. In certain embodiments, y is 4.

In certain embodiments, h is 1. In certain embodiments, h is 2. Incertain embodiments, h is 3.

In certain embodiments, y is 2; and h is 1. In certain embodiments, y is3; and h is 1. In certain embodiments, y is 4; and h is 1.

In certain embodiments, all instances of R^(B8) are the same. In certainembodiments, two instances of R^(B8) are different from each other. Incertain embodiments, at least one instance of R^(B8) is halogen (e.g.,F, Cl, Br, or I). In certain embodiments, at least one instance ofR^(B8) is substituted or unsubstituted alkyl (e.g., substituted orunsubstituted C₁₋₆ alkyl). In certain embodiments, at least one instanceof R^(B8) is —CH₃. In certain embodiments, at least one instance ofR^(B8) is —CF₃, Bn, unsubstituted ethyl, perfluoroethyl, unsubstitutedpropyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl.

In certain embodiments, g is 0. In certain embodiments, g is 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, or 13.

In certain embodiments, R^(B9) is hydrogen, substituted or unsubstitutedC₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl, substituted orunsubstituted C₂₋₆ alkynyl, substituted or unsubstituted carbocyclyl,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, a nitrogen protecting group,or of any one of Formulae (ii-1) to (ii-23). In certain embodiments,R^(B9) is H. In certain embodiments, R^(B9) is substituted orunsubstituted C₁₋₆ alkyl (e.g., C₁₋₆ alkyl substituted with one or moresubstituents independently selected from the group consisting of oxo;halogen; substituted or unsubstituted C₂₋₆ alkenyl; substituted orunsubstituted cyclopropyl; substituted or unsubstituted, 4- to7-membered monocyclic carbocyclyl comprising 1 or 2 double bonds in thecarbocyclic ring system; substituted or unsubstituted oxiranyl;substituted or unsubstituted, 5- to 10-membered, monocyclic or bicyclicheteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring systemare independently oxygen, nitrogen, or sulfur; —CN; —(C═O)R^(a);—N(R^(a))(C═O)R^(a); —O(C═O)R^(a); —OR^(a); and —N(R^(a))₂). In certainembodiments, R^(B9) is substituted or unsubstituted C₂₋₆ alkenyl (e.g.,substituted or unsubstituted vinyl). In certain embodiments, R^(B9) issubstituted or unsubstituted C₂₋₆ alkynyl (e.g., substituted orunsubstituted ethynyl). In certain embodiments, R^(B9) is substituted orunsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to7-membered, monocyclic carbocyclyl comprising zero, one, or two doublebonds in the carbocyclic ring system). In certain embodiments, R^(B9) is—C(═O)R^(a). In certain embodiments, R^(B9) is —C(═O)(substituted orunsubstituted alkyl) (e.g., —C(═O)(substituted or unsubstituted C₁₋₆alkyl), such as —C(═O)Et). In certain embodiments, R^(B9) is—C(═O)(substituted or unsubstituted alkenyl) (e.g., —C(═O)(substitutedor unsubstituted C₂₋₆ alkenyl), such as —C(═O)—CH═CH₂). In certainembodiments, R^(B9) is —C(═O)(substituted or unsubstituted carbocyclyl).In certain embodiments, R^(B9) is —C(═O)(substituted or unsubstitutedheterocyclyl). In certain embodiments, R^(B9) is —C(═O)(substituted orunsubstituted phenyl). In certain embodiments, R^(B9) is—C(═O)(substituted or unsubstituted heteroaryl). In certain embodiments,R^(B9) is —C(═O)OR^(a) (e.g., —C(═O)O(substituted or unsubstitutedalkyl) or —C(═O)O(substituted or unsubstituted phenyl)) or—C(═O)N(R^(a))₂ (e.g., —C(═O)NH₂, —C(═O)NH(substituted or unsubstitutedalkyl), —C(═O)NH(substituted or unsubstituted phenyl),—C(═O)N(substituted or unsubstituted alkyl)-(substituted orunsubstituted alkyl), or —C(═O)N(substituted or unsubstitutedphenyl)-(substituted or unsubstituted alkyl)). In certain embodiments,R^(B9) is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc,trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certainembodiments, R^(B9) is of any one of Formulae (ii-1) to (ii-23). Incertain embodiments, R^(B9) is of any one of Formulae (ii-24) to(ii-42). In certain embodiments, R^(B9) is of Formula (ii-1) (e.g., ofthe formula:

In certain embodiments, R^(B9) is of Formula (ii-3) (e.g., of theformula:

In certain embodiments, R^(B9) is of any one of the formulae shown inTable 1A. The moieties included in R^(B9) are as described herein.

In certain embodiments, a compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof, wherein R^(b) is substituted or unsubstituted C₂₋₆alkenyl.

In certain embodiments, a compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof, wherein R^(b) is substituted or unsubstituted C₂₋₆alkenyl.

In certain embodiments, a compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof, wherein R^(b) is substituted or unsubstituted C₂₋₆alkenyl.

In certain embodiments, a compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof, wherein R^(b) is substituted or unsubstituted C₂₋₆alkenyl.

Exemplary compounds of Formula (II) include, but are not limited to:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopic ally labeledderivatives, and prodrugs thereof.

Compounds of Formula (III)

In certain embodiments, a compound described herein is of Formula (III):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof, wherein:

each instance of R^(C1) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(c), —N(R^(c))₂,—SR^(c), —CN, —SCN, —C(═NR^(c))R^(c), —C(═NR^(c))OR^(c),—C(═NR^(c))N(R^(c))₂, —C(═O)R^(c), —C(═O)OR^(c), —C(═O)N(R^(c))₂, —NO₂,—NR^(c)C(═O)R^(c), —NR^(c)(═O)OR^(c), —NR^(c)C(═O)N(R^(c))₂,—OC(═O)R^(c), —OC(═O)OR^(c), or —OC(═O)N(R^(c))₂;

each instance of R^(c) is independently hydrogen, substituted orunsubstituted acyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl a nitrogen protecting group when attached to a nitrogen atom,an oxygen protecting group when attached to an oxygen atom, or a sulfurprotecting group when attached to a sulfur atom, or two instances ofR^(c) are joined to form a substituted or unsubstituted, heterocyclicring, or substituted or unsubstituted, heteroaryl ring;

r is 0, 1, 2, 3, 4, or 5;

L^(C) is —O— or —S—;

each instance of R^(C2) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(c), —N(R^(c))₂,—SR^(c), —CN, —SCN, —C(═NR^(c))R^(c), —C(═NR^(c))OR^(c),—C(═NR^(c))N(R^(c))₂, —C(═O)R^(c), —C(═O)OR^(c), —C(═O)N(R^(c))₂, —NO₂,—NR^(c)C(═O)R^(c), —NR^(c)C(═O)OR^(c), —NR^(c)C(═O)N(R^(c))₂,—OC(═O)R^(c), —OC(═O)OR^(c), or —OC(═O)N(R^(c))₂;

s is 0, 1, or 2;

R^(C3) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group;

Ring C3 is a substituted or unsubstituted, pyrimidinyl ring orsubstituted or unsubstituted, pyrazolyl ring;

each instance of R^(C4) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(c), —N(R^(c))₂,—SR^(c), —CN, —SCN, —C(═NR^(c))R^(c), —C(═NR^(c))OR^(c),—C(═NR^(c))N(R^(c))₂, —C(═O)R^(c), —C(═O)OR^(c), —C(═O)N(R^(c))₂, —NO₂,—NR^(c)C(═O)R^(c), —NR^(c)C(═O)OR^(c), —NR^(c)C(═O)N(R^(c))₂,—OC(═O)R^(c), —OC(═O)OR^(c), or —OC(═O)N(R^(c))₂;

t is 0, 1, or 2; and

R^(C5) is hydrogen, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —OR^(c), —N(R^(c))₂, —SR^(c),—CN, —SCN, —C(═NR^(c))R^(c), —C(═NR^(c))OR^(c), —C(═NR^(c))N(R^(c))₂,—C(═O)R^(c), —C(═O)OR^(c), —C(═O)N(R^(c))₂, —NO₂, —NR^(c)C(═O)R^(c),—NR^(c)C(═O)OR^(c), —NR^(c)C(═O)N(R^(c))₂, —OC(═O)R^(c), —OC(═O)OR^(c),or —OC(═O)N(R^(c))₂.

Formula (III) includes as Ring C1 a phenyl ring that is unsubstituted(e.g., when r is 0) or substituted (e.g., when r is 1, 2, 3, 4, or 5)with one or more substituents R^(C1). In certain embodiments, Ring C1 isunsubstituted phenyl. In certain embodiments, Ring C1 is of the formula:

In certain embodiments, Ring C1 is of the formula:

In Formula (III), Ring C1 may include one or more substituents R^(C1).In certain embodiments, all instances of R^(C1) are the same. In certainembodiments, two instances of R^(C1) are different from each other. Incertain embodiments, at least one instance of R^(C1) is halogen (e.g.,F, Cl, Br, or I). In certain embodiments, at least one instance ofR^(C1) is substituted or unsubstituted alkyl (e.g., substituted orunsubstituted C₁₋₆ alkyl). In certain embodiments, at least one instanceof R^(C1) is —CH₃. In certain embodiments, at least one instance ofR^(C1) is —CF₃, Bn, unsubstituted ethyl, perfluoroethyl, unsubstitutedpropyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl. Incertain embodiments, at least one instance of R^(C1) is substituted orunsubstituted alkenyl (e.g., substituted or unsubstituted C₂₋₆ alkenyl).In certain embodiments, at least one instance of R^(C1) is substitutedor unsubstituted alkynyl (e.g., substituted or unsubstituted C₁₋₆alkynyl). In certain embodiments, at least one instance of R^(C1) issubstituted or unsubstituted carbocyclyl (e.g., substituted orunsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero,one, or two double bonds in the carbocyclic ring system). In certainembodiments, at least one instance of R^(C1) is substituted orunsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to9-membered, monocyclic heterocyclyl comprising zero, one, or two doublebonds in the heterocyclic ring system, wherein one, two, or three atomsin the heterocyclic ring system are independently nitrogen, oxygen, orsulfur). In certain embodiments, at least one instance of R^(C1) issubstituted or unsubstituted aryl (e.g., substituted or unsubstituted,6- to 10-membered aryl). In certain embodiments, at least one instanceof R^(C1) is substituted or unsubstituted phenyl. In certainembodiments, at least one instance of R^(C1) is substituted orunsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to6-membered, monocyclic heteroaryl, wherein one, two, three, or fouratoms in the heteroaryl ring system are independently nitrogen, oxygen,or sulfur). In certain embodiments, at least one instance of R^(C1) is—OR^(c) (e.g., —OH, —O(substituted or unsubstituted C₁₋₆ alkyl) (e.g.,—OMe, —OEt, —OPr, —OBu, or —OBn), or —O(substituted or unsubstitutedphenyl) (e.g., —OPh)). In certain embodiments, at least one instance ofR^(C1) is —SR^(c) (e.g., —SH, —S(substituted or unsubstituted C₁₋₆alkyl) (e.g., —SMe, —SEt, —SPr, —SBu, or —SBn), or —S(substituted orunsubstituted phenyl) (e.g., —SPh)). In certain embodiments, at leastone instance of R^(C1) is —N(R^(c))₂ (e.g., —NH₂, —NH(substituted orunsubstituted C₁₋₆ alkyl) (e.g., —NHMe), or —N(substituted orunsubstituted C₁₋₆ alkyl)-(substituted or unsubstituted C₁₋₆ alkyl)(e.g., —NMe₂)). In certain embodiments, at least one instance of R^(C1)is —CN, —SCN, or —NO₂. In certain embodiments, at least one instance ofR^(C1) is —C(═NR^(c))R^(c), —C(═NR^(c))OR^(c), or —C(═NR^(c))N(R^(c))₂.In certain embodiments, at least one instance of R^(C1) is —C(═O)R^(c)(e.g., —C(═O)(substituted or unsubstituted alkyl) or —C(═O)(substitutedor unsubstituted phenyl)), —C(═O)OR^(c) (e.g., —C(═O)O(substituted orunsubstituted alkyl) or —C(═O)O(substituted or unsubstituted phenyl)),or —C(═O)N(R^(c))₂ (e.g., —C(═O)NH₂, —C(═O)NH(substituted orunsubstituted alkyl), —C(═O)NH(substituted or unsubstituted phenyl),—C(═O)N(substituted or unsubstituted alkyl)-(substituted orunsubstituted alkyl), or —C(═O)N(substituted or unsubstitutedphenyl)-(substituted or unsubstituted alkyl)). In certain embodiments,at least one instance of R^(C1) is —NR^(c)C(═O)R^(c),—NR^(c)C(═O)OR^(c), or —NR^(c)C(═O)N(R^(c))₂. In certain embodiments, atleast one instance of R^(C1) is —OC(═O)R^(c), —OC(═O)OR^(c), or—OC(═O)N(R^(c))₂.

When Formula (III) includes two or more instances of substituent R^(c),any two instances of R^(c) may be the same or different from each other.In certain embodiments, at least one instance of R^(c) is H. In certainembodiments, each instance of R^(c) is H. In certain embodiments, atleast one instance of R^(c) is substituted or unsubstituted acyl (e.g.,acetyl). In certain embodiments, at least one instance of R^(c) issubstituted or unsubstituted alkyl (e.g., substituted or unsubstitutedC₁₋₆ alkyl). In certain embodiments, at least one instance of R^(c) is—CH₃. In certain embodiments, at least one instance of R^(c) is —CF₃,Bn, unsubstituted ethyl, perfluoroethyl, unsubstituted propyl,perfluoropropyl, unsubstituted butyl, or perfluorobutyl. In certainembodiments, at least one instance of R^(c) is substituted orunsubstituted alkenyl (e.g., substituted or unsubstituted C₂₋₆ alkenyl).In certain embodiments, at least one instance of R^(c) is substituted orunsubstituted alkynyl (e.g., substituted or unsubstituted C₁₋₆ alkynyl).In certain embodiments, at least one instance of R^(c) is substituted orunsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to7-membered, monocyclic carbocyclyl comprising zero, one, or two doublebonds in the carbocyclic ring system). In certain embodiments, at leastone instance of R^(c) is substituted or unsubstituted heterocyclyl(e.g., substituted or unsubstituted, 3- to 9-membered, monocyclicheterocyclyl comprising zero, one, or two double bonds in theheterocyclic ring system, wherein one, two, or three atoms in theheterocyclic ring system are independently nitrogen, oxygen, or sulfur).In certain embodiments, at least one instance of R^(c) is substituted orunsubstituted aryl (e.g., substituted or unsubstituted, 6- to10-membered aryl). In certain embodiments, at least one instance ofR^(c) is substituted or unsubstituted phenyl. In certain embodiments, atleast one instance of R^(c) is substituted or unsubstituted heteroaryl(e.g., substituted or unsubstituted, 5- to 6-membered, monocyclicheteroaryl, wherein one, two, three, or four atoms in the heteroarylring system are independently nitrogen, oxygen, or sulfur). In certainembodiments, at least one instance of R^(c) is a nitrogen protectinggroup (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl,acetyl, or Ts) when attached to a nitrogen atom. In certain embodiments,R^(c) is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS,TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) whenattached to an oxygen atom. In certain embodiments, R^(c) is a sulfurprotecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to asulfur atom. In certain embodiments, two instances of R^(c) are joinedto form a substituted or unsubstituted, heterocyclic ring (e.g.,substituted or unsubstituted, 5- to 6-membered, monocyclic heterocyclicring comprising zero, one, or two double bonds in the heterocyclic ringsystem, wherein one, two, or three atoms in the heterocyclic ring systemare independently nitrogen, oxygen, or sulfur). In certain embodiments,two instances of R^(c) are joined to form a substituted or unsubstitutedheteroaryl ring (e.g., substituted or unsubstituted, 5- to 6-membered,monocyclic heteroaryl ring, wherein one, two, three, or four atoms inthe heteroaryl ring system are independently nitrogen, oxygen, orsulfur).

In certain embodiments, r is 0. In certain embodiments, r is 1. Incertain embodiments, r is 2. In certain embodiments, r is 3. In certainembodiments, r is 4. In certain embodiments, r is 5.

Formula (III) includes divalent linker L^(C) connecting Ring C1 to the7-azabenzothiazolyl ring. In certain embodiments, L^(C) is —O—. Incertain embodiments, L^(C) is —S—.

In Formula (III), the 7-azabenzothiazolyl ring may include one or twosubstituents R^(C2). In certain embodiments, two instances of R^(C2) arethe same. In certain embodiments, two instances of R^(C2) are differentfrom each other. In certain embodiments, at least one instance of R^(C2)is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least oneinstance of R^(C2) is substituted or unsubstituted alkyl (e.g.,substituted or unsubstituted C₁₋₆ alkyl). In certain embodiments, atleast one instance of R^(C2) is —CH₃. In certain embodiments, at leastone instance of R^(C2) is —CF₃, Bn, unsubstituted ethyl, perfluoroethyl,unsubstituted propyl, perfluoropropyl, unsubstituted butyl, orperfluorobutyl. In certain embodiments, at least one instance of R^(C2)is substituted or unsubstituted alkenyl (e.g., substituted orunsubstituted C₂₋₆ alkenyl). In certain embodiments, at least oneinstance of R^(C2) is substituted or unsubstituted alkynyl (e.g.,substituted or unsubstituted C₁₋₆ alkynyl). In certain embodiments, atleast one instance of R^(C2) is substituted or unsubstituted carbocyclyl(e.g., substituted or unsubstituted, 3- to 7-membered, monocycliccarbocyclyl comprising zero, one, or two double bonds in the carbocyclicring system). In certain embodiments, at least one instance of R^(C2) issubstituted or unsubstituted heterocyclyl (e.g., substituted orunsubstituted, 3- to 9-membered, monocyclic heterocyclyl comprisingzero, one, or two double bonds in the heterocyclic ring system, whereinone, two, or three atoms in the heterocyclic ring system areindependently nitrogen, oxygen, or sulfur). In certain embodiments, atleast one instance of R^(C2) is substituted or unsubstituted aryl (e.g.,substituted or unsubstituted, 6- to 10-membered aryl). In certainembodiments, at least one instance of R^(C2) is substituted orunsubstituted phenyl. In certain embodiments, at least one instance ofR^(C2) is substituted or unsubstituted heteroaryl (e.g., substituted orunsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one,two, three, or four atoms in the heteroaryl ring system areindependently nitrogen, oxygen, or sulfur). In certain embodiments, atleast one instance of R^(C2) is —OR^(c) (e.g., —OH, —O(substituted orunsubstituted C₁₋₆ alkyl) (e.g., —OMe, —OEt, —OPr, —OBu, or —OBn), or—O(substituted or unsubstituted phenyl) (e.g., —OPh)). In certainembodiments, at least one instance of R^(C2) is —SR^(c) (e.g., —SH,—S(substituted or unsubstituted C₁₋₆ alkyl) (e.g., —SMe, —SEt, —SPr,—SBu, or —SBn), or —S(substituted or unsubstituted phenyl) (e.g.,—SPh)). In certain embodiments, at least one instance of R^(C2) is—N(R^(C))₂ (e.g., —NH₂, —NH(substituted or unsubstituted C₁₋₆ alkyl)(e.g., —NHMe), or —N(substituted or unsubstituted C₁₋₆alkyl)-(substituted or unsubstituted C₁₋₆ alkyl) (e.g., —NMe₂)). Incertain embodiments, at least one instance of R^(C2) is —CN, —SCN, or—NO₂. In certain embodiments, at least one instance of R^(C2) is—C(═NR^(c))R^(c), —C(═NR^(c))OR^(c), or —C(═NR^(c))N(R^(c))₂. In certainembodiments, at least one instance of R^(C2) is —C(═O)R^(c) (e.g.,—C(═O)(substituted or unsubstituted alkyl) or —C(═O)(substituted orunsubstituted phenyl)), —C(═O)OR^(c) (e.g., —C(═O)O(substituted orunsubstituted alkyl) or —C(═O)O(substituted or unsubstituted phenyl)),or —C(═O)N(R^(c))₂ (e.g., —C(═O)NH₂, —C(═O)NH(substituted orunsubstituted alkyl), —C(═O)NH(substituted or unsubstituted phenyl),—C(═O)N(substituted or unsubstituted alkyl)-(substituted orunsubstituted alkyl), or —C(═O)N(substituted or unsubstitutedphenyl)-(substituted or unsubstituted alkyl)). In certain embodiments,at least one instance of R^(C2) is —NR^(c)C(═O)R^(c),—NR^(c)C(═O)OR^(c), or —NR^(c)C(═O)N(R^(c))₂. In certain embodiments, atleast one instance of R^(C2) is —OC(═O)R^(c), —OC(═O)OR^(c), or—OC(═O)N(R^(c))₂.

In certain embodiments, s is 0. In certain embodiments, s is 1. Incertain embodiments, s is 2.

Formula (III) includes substituent R^(C3) on a nitrogen atom attached tothe 7-azabenzothiazolyl ring. In certain embodiments, R^(C3) is H. Incertain embodiments, R^(C3) is substituted or unsubstituted C₁₋₆ alkyl(e.g., —CH₃, Bn, —CF₃, unsubstituted ethyl, perfluoroethyl,unsubstituted propyl, perfluoropropyl, unsubstituted butyl, orperfluorobutyl). In certain embodiments, R^(C3) is a nitrogen protectinggroup (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl,acetyl, or Ts).

Formula (III) includes Ring C3. In certain embodiments, Ring C3 is apyrimidinyl ring that is unsubstituted (e.g., when t is 0) orsubstituted (e.g., when t is 1 or 2) with one or more substituentsR^(C4). In certain embodiments, Ring C3 is of the formula:

In certain embodiments, in Formula (III), when Ring C3 is a substitutedor unsubstituted pyrimidinyl ring, the carbon atom labeled with “2” isattached to R^(C5), and the carbon atom labeled with “4” is attached tothe nitrogen atom to which R^(C3) is attached. In certain embodiments,Ring C3 is of the formula:

In certain embodiments, Ring C3 is of the formula:

In certain embodiments, Ring C3 is a pyrazolyl ring that isunsubstituted (e.g., when t is 0) or substituted (e.g., when t is 1 or2) with one or more substituents R^(C4). In certain embodiments, Ring C3is of the formula:

In certain embodiments, in Formula (III), when Ring C3 is a substitutedor unsubstituted pyrazolyl ring, the nitrogen atom labeled with “1” isattached to R^(C5), and the carbon atom labeled with “3” is attached tothe nitrogen atom to which R^(C3) is attached. In certain embodiments,Ring C3 is of the formula:

In certain embodiments, Ring C3 is of the formula:

In certain embodiments, Ring C3 is of the formula:

In certain embodiments, Ring C3 is of the formula:

In certain embodiments, Ring C3 is of the formula:

In Formula (III), Ring C3 may include one or two substituents R^(C4). Incertain embodiments, two instances of R^(C4) are the same. In certainembodiments, two instances of R^(C4) are different from each other. Incertain embodiments, at least one instance of R^(C4) is halogen (e.g.,F, Cl, Br, or I). In certain embodiments, at least one instance ofR^(C4) is substituted or unsubstituted alkyl (e.g., substituted orunsubstituted C₁₋₆ alkyl). In certain embodiments, at least one instanceof R^(C4) is —CH₃. In certain embodiments, at least one instance ofR^(C4) is —CF₃, Bn, unsubstituted ethyl, perfluoroethyl, unsubstitutedpropyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl. Incertain embodiments, at least one instance of R^(C4) is substituted orunsubstituted alkenyl (e.g., substituted or unsubstituted C₂₋₆ alkenyl).In certain embodiments, at least one instance of R^(C4) is substitutedor unsubstituted alkynyl (e.g., substituted or unsubstituted C₁₋₆alkynyl). In certain embodiments, at least one instance of R^(C4) issubstituted or unsubstituted carbocyclyl (e.g., substituted orunsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero,one, or two double bonds in the carbocyclic ring system). In certainembodiments, at least one instance of R^(C4) is substituted orunsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to9-membered, monocyclic heterocyclyl comprising zero, one, or two doublebonds in the heterocyclic ring system, wherein one, two, or three atomsin the heterocyclic ring system are independently nitrogen, oxygen, orsulfur). In certain embodiments, at least one instance of R^(C4) issubstituted or unsubstituted aryl (e.g., substituted or unsubstituted,6- to 10-membered aryl). In certain embodiments, at least one instanceof R^(C4) is substituted or unsubstituted phenyl. In certainembodiments, at least one instance of R^(C4) is substituted orunsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to6-membered, monocyclic heteroaryl, wherein one, two, three, or fouratoms in the heteroaryl ring system are independently nitrogen, oxygen,or sulfur). In certain embodiments, at least one instance of R^(C4) is—OR^(c) (e.g., —OH, —O(substituted or unsubstituted C₁₋₆ alkyl) (e.g.,—OMe, —OEt, —OPr, —OBu, or —OBn), or —O(substituted or unsubstitutedphenyl) (e.g., —OPh)). In certain embodiments, at least one instance ofR^(C4) is —SR^(c) (e.g., —SH, —S(substituted or unsubstituted C₁₋₆alkyl) (e.g., —SMe, —SEt, —SPr, —SBu, or —SBn), or —S(substituted orunsubstituted phenyl) (e.g., —SPh)). In certain embodiments, at leastone instance of R^(C4) is —N(R^(c))₂ (e.g., —NH₂, —NH(substituted orunsubstituted C₁₋₆ alkyl) (e.g., —NHMe), or —N(substituted orunsubstituted C₁₋₆ alkyl)-(substituted or unsubstituted C₁₋₆ alkyl)(e.g., —NMe₂)). In certain embodiments, at least one instance of R^(C4)is —CN, —SCN, or —NO₂. In certain embodiments, at least one instance ofR^(C4) is —C(═NR^(c))R^(c), —C(═NR^(c))OR^(c), or —C(═NR^(c))N(R^(c))₂.In certain embodiments, at least one instance of R^(C4) is —C(═O)R^(c)(e.g., —C(═O)(substituted or unsubstituted alkyl) or —C(═O)(substitutedor unsubstituted phenyl)), —C(═O)OR^(c) (e.g., —C(═O)O(substituted orunsubstituted alkyl) or —C(═O)O(substituted or unsubstituted phenyl)),or —C(═O)N(R^(c))₂ (e.g., —C(═O)NH₂, —C(═O)NH(substituted orunsubstituted alkyl), —C(═O)NH(substituted or unsubstituted phenyl),—C(═O)N(substituted or unsubstituted alkyl)-(substituted orunsubstituted alkyl), or —C(═O)N(substituted or unsubstitutedphenyl)-(substituted or unsubstituted alkyl)). In certain embodiments,at least one instance of R^(C4) is —NR^(c)C(═O)R^(c),—NR^(c)C(═O)OR^(c), or —NR^(c)C(═O)N(R^(c))₂. In certain embodiments, atleast one instance of R^(C4) is —OC(═O)R^(c), —OC(═O)OR^(c), or—OC(═O)N(R^(c))₂.

In certain embodiments, t is 0. In certain embodiments, t is 1. Incertain embodiments, t is 2.

Formula (III) includes substituent R^(C5) on a nitrogen atom attached toRing C3. In certain embodiments, R^(C5) is H. In certain embodiments,R^(C5) is halogen (e.g., F, Cl, Br, or I). In certain embodiments,R^(C5) is substituted or unsubstituted alkyl (e.g., substituted orunsubstituted C₁₋₆ alkyl). In certain embodiments, R^(C5) is —CH₃. Incertain embodiments, R^(C5) is —CF₃, Bn, unsubstituted ethyl,perfluoroethyl, unsubstituted propyl, perfluoropropyl, unsubstitutedbutyl, or perfluorobutyl. In certain embodiments, R^(C5) is substitutedor unsubstituted alkenyl (e.g., substituted or unsubstituted C₂₋₆alkenyl). In certain embodiments, R^(C5) is substituted or unsubstitutedalkynyl (e.g., substituted or unsubstituted C₁₋₆ alkynyl). In certainembodiments, R^(C5) is substituted or unsubstituted carbocyclyl (e.g.,substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclylcomprising zero, one, or two double bonds in the carbocyclic ringsystem). In certain embodiments, R^(C5) is substituted or unsubstitutedheterocyclyl (e.g., substituted or unsubstituted, 3- to 9-membered,monocyclic heterocyclyl comprising zero, one, or two double bonds in theheterocyclic ring system, wherein one, two, or three atoms in theheterocyclic ring system are independently nitrogen, oxygen, or sulfur).In certain embodiments, R^(C5) is substituted or unsubstitutedtetrahydropyranyl or substituted or unsubstituted piperidinyl. Incertain embodiments, R^(C5) is of the formula:

wherein R¹ is H, substituted or unsubstituted C₁₋₆ alkyl, or a nitrogenprotecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl,triphenylmethyl, acetyl, or Ts). In certain embodiments, R^(C5) issubstituted or unsubstituted oxetanyl, substituted or unsubstitutedazetidinyl, substituted or unsubstituted tetrahydrofuranyl, substitutedor unsubstituted pyrrolidinyl, substituted or unsubstituted morpholinyl,or substituted or unsubstituted piperazinyl. In certain embodiments,R^(C5) is substituted or unsubstituted aryl (e.g., substituted orunsubstituted, 6- to 10-membered aryl). In certain embodiments, R^(C5)is substituted or unsubstituted phenyl. In certain embodiments, R^(C5)is substituted or unsubstituted heteroaryl (e.g., substituted orunsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one,two, three, or four atoms in the heteroaryl ring system areindependently nitrogen, oxygen, or sulfur). In certain embodiments,R^(C5) is —OR^(a) (e.g., —OH, —O(substituted or unsubstituted C₁₋₆alkyl) (e.g., —OMe, —OEt, —OPr, —OBu, or —OBn), or —O(substituted orunsubstituted phenyl) (e.g., —OPh)). In certain embodiments, R^(C5) is—SR^(a) (e.g., —SH, —S(substituted or unsubstituted C₁₋₆ alkyl) (e.g.,—SMe, —SEt, —SPr, —SBu, or —SBn), or —S(substituted or unsubstitutedphenyl) (e.g., —SPh)). In certain embodiments, R^(C5) is —N(R^(a))₂(e.g., —NH₂, —NH(substituted or unsubstituted C₁₋₆ alkyl) (e.g., —NHMe),or —N(substituted or unsubstituted C₁₋₆ alkyl)-(substituted orunsubstituted C₁₋₆ alkyl) (e.g., —NMe₂)). In certain embodiments, R^(C5)is —CN, —SCN, or —NO₂. In certain embodiments, R^(C5) is—C(═NR^(a))R^(a), —C(═NR^(a))OR^(a), or —C(═NR^(a))N(R^(a))₂. In certainembodiments, R^(C5) is —C(═O)R^(a) (e.g., —C(═O)(substituted orunsubstituted alkyl) or —C(═O)(substituted or unsubstituted phenyl)),—C(═O)OR^(a) (e.g., —C(═O)O(substituted or unsubstituted alkyl) or—C(═O)O(substituted or unsubstituted phenyl)), or —C(═O)N(R^(a))₂ (e.g.,—C(═O)NH₂, —C(═O)NH(substituted or unsubstituted alkyl),—C(═O)NH(substituted or unsubstituted phenyl), —C(═O)N(substituted orunsubstituted alkyl)-(substituted or unsubstituted alkyl), or—C(═O)N(substituted or unsubstituted phenyl)-(substituted orunsubstituted alkyl)). In certain embodiments, R^(C5) is—NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a), or —NR^(a)C(═O)N(R^(a))₂. Incertain embodiments, R^(C5) is —OC(═O)R^(a), —OC(═O)OR^(a), or—OC(═O)N(R^(a))₂. In certain embodiments, R^(C5) is of the formula:

wherein:

R^(C6) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group;

b is 0 or 1;

each instance of R^(C6) is independently hydrogen, halogen, orsubstituted or unsubstituted C₁₋₆ alkyl;

c is 0, 1, 2, 3, or 4;

d is 1, 2, 3, or 4;

e is 1, 2, or 3;

each instance of R^(C8) is independently halogen, or substituted orunsubstituted C₁₋₆ alkyl;

f is an integer between 0 and 13, inclusive; and

R^(C9) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, substitutedor unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstituted carbocyclyl, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)N(R^(a))₂, a nitrogen protecting group, or of anyone of Formulae (ii-1) to (ii-42):

wherein:

L³ is a bond or an optionally substituted CA hydrocarbon chain,optionally wherein one or more carbon units of the hydrocarbon chain areindependently replaced with —O—, —S—, —NR^(L3a)—, —NR^(L3a)C(═O)—,—C(═O)NR^(L3a)—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—,—NR^(L3a)C(═S)—, —C(═S)NR^(L3a)—, trans-CR^(L3b)═CR^(L3b)—,cis-CR^(L3b)═CR^(L3b)—, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—,—S(═O)NR^(L3a)—, —NR^(L3a)S(═O)—, —S(═O)₂—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR^(L3a)—, or —NR^(L3a)S(═O)₂—, wherein R^(L3a) is hydrogen,substituted or unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group,and wherein each occurrence of R^(L3b) is independently selected fromthe group consisting of hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, ortwo R^(L3b) groups are joined to form an optionally substitutedcarbocyclic or optionally substituted heterocyclic ring;

L⁴ is a bond or an optionally substituted C₁₋₄ hydrocarbon chain;

R^(E1) is selected from the group consisting of hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —CN, —CH₂OR^(E1a), —CH₂N(R^(E1a))₂,—CH₂SR^(E1a), —OR^(E1a), —N(R^(E1a))₂, —Si(R^(E1a))₃, and —SR^(E1a),wherein each occurrence of R^(E1a) is independently selected from thegroup consisting of hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or two R^(E1a)groups are joined to form an optionally substituted heterocyclic ring;

R^(E2) is selected from the group consisting of hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —CN, —CH₂OR^(E2a), —CH₂N(R^(E2a))₂,—CH₂SR^(E2a), —OR^(E2a), —N(R^(E2a))₂, and —SR^(E2a), wherein eachoccurrence of R^(E2a) is independently selected from the groupconsisting of hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or two R^(E2a)groups are joined to form an optionally substituted heterocyclic ring;

R^(E3) is selected from the group consisting of hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —CN, —CH₂OR^(E3a), —CH₂N(R^(E3a))₂,—CH₂SR^(E3a), —OR^(E3a), —N(R^(E3a))₂, and —SR^(E3a), wherein eachoccurrence of R^(E3a) is independently selected from the groupconsisting of hydrogen, optionally substituted alkyl, optionallysubstituted alkoxy, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or two R^(E3a) groups are joined to form anoptionally substituted heterocyclic ring;

or R^(E1) and R^(E3), or R^(E2) and R^(E3), or R^(E1) and R^(E2) arejoined to form an optionally substituted carbocyclic or optionallysubstituted heterocyclic ring;

R^(E4) is a leaving group;

R^(E5) is halogen;

Y is O, S, or NR^(E6), wherein R^(E6) is hydrogen, substituted orunsubstituted C₁₋₆ alkyl, or a nitrogen protecting group;

a is 1 or 2; and

each instance of z is independently 0, 1, 2, 3, 4, 5, or 6.

In certain embodiments, R^(C5) is of the formula:

In certain embodiments, R^(C5) is of the formula:

In certain embodiments, R^(C5) is of the formula:

wherein R^(c) is substituted or unsubstituted C₂₋₆ alkenyl. In certainembodiments, R^(C5) is of the formula:

wherein R^(c) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(C5) is of the formula:

In certain embodiments, R^(C5) is of the formula:

In certain embodiments, R^(C5) is of the formula:

In certain embodiments, R^(C5) is of the formula:

In certain embodiments, R^(C5) is of the formula:

wherein R^(c) is substituted or unsubstituted C₂₋₆ alkenyl. In certainembodiments, R^(C5) is of the formula:

wherein R^(c) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(C5) is of the formula:

In certain embodiments, R^(C5) is of the formula:

In certain embodiments, R^(C6) is H. In certain embodiments, R^(C6) issubstituted or unsubstituted C₁₋₆ alkyl (e.g., —CH₃, Bn, —CF₃,unsubstituted ethyl, perfluoroethyl, unsubstituted propyl,perfluoropropyl, unsubstituted butyl, or perfluorobutyl). In certainembodiments, R^(C6) is a nitrogen protecting group (e.g., Bn, Boc, Cbz,Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

In certain embodiments, b is 0. In certain embodiments, b is 1.

In certain embodiments, b is 1; and R^(C6) is H.

In certain embodiments, all instances of R^(C7) are the same. In certainembodiments, two instances of R^(C7) are different from each other. Incertain embodiments, at least one instance of R^(C7) is H. In certainembodiments, each instance of R^(C7) is H. In certain embodiments, atleast one instance of R^(C7) is halogen (e.g., F, Cl, Br, or I). Incertain embodiments, at least one instance of R^(C7) is substituted orunsubstituted alkyl (e.g., substituted or unsubstituted C₁₋₆ alkyl). Incertain embodiments, at least one instance of R^(C7) is —CH₃. In certainembodiments, at least one instance of R^(C7) is —CF₃, Bn, unsubstitutedethyl, perfluoroethyl, unsubstituted propyl, perfluoropropyl,unsubstituted butyl, or perfluorobutyl.

In certain embodiments, c is 0. In certain embodiments, c is 1. Incertain embodiments, c is 2. In certain embodiments, c is 3. In certainembodiments, c is 4.

In certain embodiments, d is 1. In certain embodiments, d is 2. Incertain embodiments, d is 3. In certain embodiments, d is 4.

In certain embodiments, e is 1. In certain embodiments, e is 2. Incertain embodiments, e is 3.

In certain embodiments, d is 2; and e is 1. In certain embodiments, d is3; and e is 1. In certain embodiments, d is 4; and e is 1.

In certain embodiments, all instances of R^(C8) are the same. In certainembodiments, two instances of R^(C8) are different from each other. Incertain embodiments, at least one instance of R^(C8) is halogen (e.g.,F, Cl, Br, or I). In certain embodiments, at least one instance ofR^(C8) is substituted or unsubstituted alkyl (e.g., substituted orunsubstituted C₁₋₆ alkyl). In certain embodiments, at least one instanceof R^(C8) is —CH₃. In certain embodiments, at least one instance ofR^(C8) is —CF₃, Bn, unsubstituted ethyl, perfluoroethyl, unsubstitutedpropyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl.

In certain embodiments, f is 0. In certain embodiments, f is 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, or 13.

In certain embodiments, R^(C9) is hydrogen, substituted or unsubstitutedC₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl, substituted orunsubstituted C₂₋₆ alkynyl, substituted or unsubstituted carbocyclyl,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, a nitrogen protecting group,or of any one of Formulae (ii-1) to (ii-23). In certain embodiments,R^(C9) is H. In certain embodiments, R^(C9) is substituted orunsubstituted C₁₋₆ alkyl (e.g., C₁₋₆ alkyl substituted with one or moresubstituents independently selected from the group consisting of oxo;halogen; substituted or unsubstituted C₂₋₆ alkenyl; substituted orunsubstituted cyclopropyl; substituted or unsubstituted, 4- to7-membered monocyclic carbocyclyl comprising 1 or 2 double bonds in thecarbocyclic ring system; substituted or unsubstituted oxiranyl;substituted or unsubstituted, 5- to 10-membered, monocyclic or bicyclicheteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring systemare independently oxygen, nitrogen, or sulfur; —CN; —(C═O)R^(a);—N(R^(a))(C═O)R^(a); —O(C═O)R^(a); —OR^(a); and —N(R^(a))₂). In certainembodiments, R^(C9) is substituted or unsubstituted C₂₋₆ alkenyl (e.g.,substituted or unsubstituted vinyl). In certain embodiments, R^(C9) issubstituted or unsubstituted C₂₋₆ alkynyl (e.g., substituted orunsubstituted ethynyl). In certain embodiments, R^(C9) is substituted orunsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to7-membered, monocyclic carbocyclyl comprising zero, one, or two doublebonds in the carbocyclic ring system). In certain embodiments, R^(C9) is—C(═O)R^(a). In certain embodiments, R^(C9) is —C(═O)(substituted orunsubstituted alkyl) (e.g., —C(═O)(substituted or unsubstituted C₁₋₆alkyl), such as —C(═O)Et). In certain embodiments, R^(C9) is—C(═O)(substituted or unsubstituted alkenyl) (e.g., —C(═O)(substitutedor unsubstituted C₂₋₆ alkenyl), such as —C(═O)—CH═CH₂). In certainembodiments, R^(C9) is —C(═O)(substituted or unsubstituted carbocyclyl).In certain embodiments, R^(C9) is —C(═O)(substituted or unsubstitutedheterocyclyl). In certain embodiments, R^(C9) is —C(═O)(substituted orunsubstituted phenyl). In certain embodiments, R^(C9) is—C(═O)(substituted or unsubstituted heteroaryl). In certain embodiments,R^(C9) is —C(═O)OR^(a) (e.g., —C(═O)O(substituted or unsubstitutedalkyl) or —C(═O)O(substituted or unsubstituted phenyl)) or—C(═O)N(R^(a))₂ (e.g., —C(═O)NH₂, —C(═O)NH(substituted or unsubstitutedalkyl), —C(═O)NH(substituted or unsubstituted phenyl),—C(═O)N(substituted or unsubstituted alkyl)-(substituted orunsubstituted alkyl), or —C(═O)N(substituted or unsubstitutedphenyl)-(substituted or unsubstituted alkyl)). In certain embodiments,R^(C9) is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc,trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certainembodiments, R^(C9) is of any one of Formulae (ii-1) to (ii-23). Incertain embodiments, R^(C9) is of any one of Formulae (ii-24) to(ii-42). In certain embodiments, R^(C9) is of Formula (ii-1) (e.g., ofthe formula:

In certain embodiments, R^(C9) is of Formula (ii-3) (e.g., of theformula:

In certain embodiments, R^(C9) is of any one of the formulae shown inTable 1A. The moieties included in R^(C9) are as described herein.

In certain embodiments, a compound of Formula (III) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (III) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (III) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (III) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof, wherein R^(c) is substituted or unsubstituted C₂₋₆alkenyl.

In certain embodiments, a compound of Formula (III) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (III) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (III) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (III) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (III) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (III) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

Exemplary compounds of Formula (III) include, but are not limited to:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopic ally labeledderivatives, and prodrugs thereof.

PHARMACEUTICAL COMPOSITIONS, KITS, AND ADMINISTRATION

The present disclosure provides pharmaceutical compositions comprising acompound described herein, or a pharmaceutically acceptable saltthereof, and optionally a pharmaceutically acceptable excipient. Incertain embodiments, a pharmaceutical composition described hereincomprises a compound described herein, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient. Thepharmaceutical compositions described herein may be useful in treatingand/or preventing proliferative diseases (e.g., myelodysplasia,leukemia, lymphoma (e.g., Waldenström's macroglobulinemia)) in asubject, inhibiting the activity of a protein kinase (e.g., HCK, BTK) ina subject, biological sample, tissue, or cell, and/or inducing apoptosisin a cell.

In certain embodiments, a subject described herein is an animal. Theanimal may be of either sex and may be at any stage of development. Incertain embodiments, a subject described herein described herein is ahuman. In certain embodiments, a subject described herein is a non-humananimal. In certain embodiments, a subject described herein is a mammal(e.g., non-human mammal). In certain embodiments, a subject describedherein is a domesticated animal, such as a dog, cat, cow, pig, horse,sheep, or goat. In certain embodiments, a subject described herein is acompanion animal such as a dog or cat. In certain embodiments, a subjectdescribed herein is a livestock animal such as a cow, pig, horse, sheep,or goat. In certain embodiments, a subject described herein is a zooanimal. In another embodiment, a subject described herein is a researchanimal such as a rodent (e.g., mouse, rat), dog, pig, or non-humanprimate. In certain embodiments, the animal is a genetically engineeredanimal. In certain embodiments, the animal is a transgenic animal (e.g.,transgenic mice and transgenic pigs). In certain embodiments, a subjectdescribed herein is a fish or reptile.

In certain embodiments, a biological sample described herein is bonemarrow, lymph node, spleen, or blood.

In certain embodiments, a tissue described herein is blood. In certainembodiments, a tissue described herein is bone marrow. In certainembodiments, a tissue described herein is a central nervous system (CNS)tissue (e.g., brain, spinal cord, meninges). In certain embodiments, atissue described herein is an immune privileged tissue. In certainembodiments, a tissue described herein is the placenta or testicle. Incertain embodiments, a tissue described herein is a fetus. In certainembodiments, a tissue described herein is the eye. In certainembodiments, a tissue described herein is the spleen. In certainembodiments, a tissue described herein is the marginal zone.

In certain embodiments, a cell described herein is in vitro. In certainembodiments, a cell described herein is ex vivo. In certain embodiments,a cell described herein is in vivo. In certain embodiments, a celldescribed herein is a malignant cell (e.g., malignant blood cell). Incertain embodiments, a cell described herein is a malignanthematopoietic stem cell (e.g., malignant myeloid cell or malignantlymphoid cell). In certain embodiments, a cell described herein is amalignant lymphocyte (e.g., malignant T-cell or malignant B-cell). Incertain embodiments, a cell described herein is a malignant red bloodcell, malignant white blood cell, or malignant platelet. In certainembodiments, a cell described herein is a malignant neutrophil,malignant macrophage, or malignant plasma cell.

In certain embodiments, the compound described herein is provided in aneffective amount in the pharmaceutical composition. In certainembodiments, the effective amount is a therapeutically effective amount(e.g., amount effective for treating a proliferative disease in asubject in need thereof). In certain embodiments, the effective amountis an amount effective for inhibiting the activity of a protein kinase(e.g., HCK, BTK) in a subject in need thereof. In certain embodiments,the effective amount is an amount effective for inhibiting the activityof a protein kinase (e.g., HCK, BTK) in a cell. In certain embodiments,the effective amount is an amount effective for inducing apoptosis in acell. In certain embodiments, the effective amount is a prophylacticallyeffective amount (e.g., amount effective for preventing a proliferativedisease in a subject in need thereof and/or for keeping a subject inneed thereof in remission of a proliferative disease).

In certain embodiments, a protein kinase described herein is HCK. Incertain embodiments, a protein kinase described herein is BTK. Incertain embodiments, a protein kinase described herein is IRAK1 orIRAK4. In certain embodiments, a protein kinase described herein is BMX.In certain embodiments, a protein kinase described herein is a PI3K. Incertain embodiments, a protein kinase described herein is ABL, ACK, ARG,BLK, CSK, EphB1, EphB2, FGR, FRK, FYN, SRC, YES, LCK, LYN, MAP2K5, NLK,PIP4K2C, p38a, SNRK, SRC, or TEC. In certain embodiments, a proteinkinase described herein is ABL1(H396P)-phosphorylated,ABL1-phosphorylated, BLK, EPHA4, EPHB2, EPHB3, EPHB4, FGR,JAK3(JH1domain-catalytic), KIT, KIT(L576P), KIT(V559D), PDGFRB, SRC,YES, ABL(H396P)-nonphosphorylated, ABL(Y253F)-phosphorylated,ABL1-nonphosphorylated, FRK, LYN, ABL1(Q252H)-nonphosphorylated, DDR1,EPHB1, ERBB4, p38-alpha, ABL2, ABL1(Q252H)-phosphorylated, SIK, EPHA8,MEK5, ABL1(E255K)-phosphorylated, ABL1(F317L)-nonphosphorylated, FYN,LCK, EPHA2, ABL(M351T)-phosphorylated, TXK, EGFR(L858R), EGFR(L861Q),ERBB2, ERBB3, EPHA5, ABL1(F317I)-nonphosphorylated, EGFR(L747-E749del,A750P), CSK, EPHA1, ABL1(F317L)-phosphorylated, BRAF(V600E), EGFR,KIT-autoinhibited, or EGFR(E746-A750del). In certain embodiments, aprotein kinase described herein is ABL1(F317L)-nonphosphorylated, AB L(H396P)-nonphosphorylated, AB L (H396P)-phosphorylated,ABL-phosphorylated, BLK, EPHA4, EPHB2, EPHB3, EPHB4,JAK3(JH1domain-catalytic), KIT, KIT(L576P), KIT(V559D), LYN, PDGFRB,SRC, YES, ABL1-nonphosphorylated, ABL1(Y253F)-phosphorylated, ERBB3,FGR, FRK, p38-alpha, ABL1(F317I)-nonphosphorylated, DDR1, EPHA2,ABL1(Q252H)-phosphorylated, MEK5, ABL1(Q252H)-nonphosphorylated, ABL2,FYN, EPHB1, ABL1(E255K)-phosphorylated, ABL1(F317L)-phosphorylated,EPHA1, ABL1(M351T)-phosphorylated, ERBB4, TXK, LCK, EPHA8, SIK, EPHA5,EGFR(L861Q), CSF1R-autoinhibited, BRAF(V600E), BRK, CSK, KIT(D816V),KIT-autoinhibited, EGFR(L747-T751del,Sins), EGFR(L858R),EGFR(L747-E749del, A750P), or CSF1R.

In certain embodiments, the effective amount is an amount effective forinhibiting the activity of a protein kinase (e.g., HCK, BTK) by at leastabout 10%, at least about 20%, at least about 30%, at least about 40%,at least about 50%, at least about 60%, at least about 70%, at leastabout 80%, at least about 90%, at least about 95%, or at least about98%. In certain embodiments, the effective amount is an amount effectivefor inhibiting the activity of a protein kinase (e.g., HCK, BTK) by notmore than 10%, not more than 20%, not more than 30%, not more than 40%,not more than 50%, not more than 60%, not more than 70%, not more than80%, not more than 90%, not more than 95%, or not more than 98%. Incertain embodiments, the effective amount is an amount effective forinhibiting the activity of a protein kinase (e.g., HCK, BTK) by a rangebetween a percentage described in this paragraph and another percentagedescribed in this paragraph, inclusive.

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include bringing the compound described herein (i.e., the“active ingredient”) into association with a carrier or excipient,and/or one or more other accessory ingredients, and then, if necessaryand/or desirable, shaping, and/or packaging the product into a desiredsingle- or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.A “unit dose” is a discrete amount of the pharmaceutical compositioncomprising a predetermined amount of the active ingredient. The amountof the active ingredient is generally equal to the dosage of the activeingredient which would be administered to a subject and/or a convenientfraction of such a dosage, such as one-half or one-third of such adosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition described herein will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.The composition may comprise between 0.1% and 100% (w/w) activeingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calciumphosphate, dicalcium phosphate, calcium sulfate, calcium hydrogenphosphate, sodium phosphate lactose, sucrose, cellulose,microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodiumchloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

Exemplary granulating and/or dispersing agents include potato starch,corn starch, tapioca starch, sodium starch glycolate, clays, alginicacid, guar gum, citrus pulp, agar, bentonite, cellulose, and woodproducts, natural sponge, cation-exchange resins, calcium carbonate,silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)(crospovidone), sodium carboxymethyl starch (sodium starch glycolate),carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose(croscarmellose), methylcellulose, pregelatinized starch (starch 1500),microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate,quaternary ammonium compounds, and mixtures thereof.

Exemplary surface active agents and/or emulsifiers include naturalemulsifiers (e.g., acacia, agar, alginic acid, sodium alginate,tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk,casein, wool fat, cholesterol, wax, and lecithin), colloidal clays(e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminumsilicate)), long chain amino acid derivatives, high molecular weightalcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetinmonostearate, ethylene glycol distearate, glyceryl monostearate, andpropylene glycol monostearate, polyvinyl alcohol), carbomers (e.g.,carboxy polymethylene, polyacrylic acid, acrylic acid polymer, andcarboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g.,carboxymethylcellulose sodium, powdered cellulose, hydroxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylenesorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60),polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate(Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate(Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80),polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45),polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil,polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters,polyethylene glycol fatty acid esters (e.g., Cremophor®),polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)),poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamineoleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyllaurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188,cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride,docusate sodium, and/or mixtures thereof.

Exemplary binding agents include starch (e.g., cornstarch and starchpaste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin,molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums(e.g., acacia, sodium alginate, extract of Irish moss, panwar gum,ghatti gum, mucilage of isapol husks, carboxymethylcellulose,methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, microcrystalline cellulose,cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate(Veegum®), and larch arabogalactan), alginates, polyethylene oxide,polyethylene glycol, inorganic calcium salts, silicic acid,polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.

Exemplary preservatives include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, antiprotozoanpreservatives, alcohol preservatives, acidic preservatives, and otherpreservatives. In certain embodiments, the preservative is anantioxidant. In other embodiments, the preservative is a chelatingagent.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, andsodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid(EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodiumedetate, trisodium edetate, calcium disodium edetate, dipotassiumedetate, and the like), citric acid and salts and hydrates thereof(e.g., citric acid monohydrate), fumaric acid and salts and hydratesthereof, malic acid and salts and hydrates thereof, phosphoric acid andsalts and hydrates thereof, and tartaric acid and salts and hydratesthereof. Exemplary antimicrobial preservatives include benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butyl paraben, methylparaben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoicacid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol,phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate,and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylatedhydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS),sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, Glydant®Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®,Kathon®, and Euxyl®.

Exemplary buffering agents include citrate buffer solutions, acetatebuffer solutions, phosphate buffer solutions, ammonium chloride, calciumcarbonate, calcium chloride, calcium citrate, calcium glubionate,calcium gluceptate, calcium gluconate, D-gluconic acid, calciumglycerophosphate, calcium lactate, propanoic acid, calcium levulinate,pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasiccalcium phosphate, calcium hydroxide phosphate, potassium acetate,potassium chloride, potassium gluconate, potassium mixtures, dibasicpotassium phosphate, monobasic potassium phosphate, potassium phosphatemixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodiumcitrate, sodium lactate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline,Ringer's solution, ethyl alcohol, and mixtures thereof.

Exemplary lubricating agents include magnesium stearate, calciumstearate, stearic acid, silica, talc, malt, glyceryl behanate,hydrogenated vegetable oils, polyethylene glycol, sodium benzoate,sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate,sodium lauryl sulfate, and mixtures thereof.

Exemplary natural oils include almond, apricot kernel, avocado, babassu,bergamot, black current seed, borage, cade, camomile, canola, caraway,carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee,corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed,geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate,jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademianut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, andwheat germ oils. Exemplary synthetic oils include, but are not limitedto, butyl stearate, caprylic triglyceride, capric triglyceride,cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate,mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixturesthereof.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugatesdescribed herein are mixed with solubilizing agents such as Cremophor®,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and mixtures thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension, or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P., and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or di-glycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform may be accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are typicallysuppositories which can be prepared by mixing the conjugates describedherein with suitable non-irritating excipients or carriers such as cocoabutter, polyethylene glycol, or a suppository wax which are solid atambient temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active ingredient.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activeingredient is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or (a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, (b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, (c) humectants such as glycerol, (d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, (e) solutionretarding agents such as paraffin, (f) absorption accelerators such asquaternary ammonium compounds, (g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolinand bentonite clay, and (i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets, and pills, thedosage form may include a buffering agent.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the art of pharmacology. Theymay optionally comprise opacifying agents and can be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain part of the intestinal tract, optionally, in a delayed manner.Examples of encapsulating compositions which can be used includepolymeric substances and waxes. Solid compositions of a similar type canbe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugar as well as high molecularweight polethylene glycols and the like.

The active ingredient can be in a micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings, and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active ingredient can be admixed with at least oneinert diluent such as sucrose, lactose, or starch. Such dosage forms maycomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may comprise bufferingagents. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of encapsulating agents which can be usedinclude polymeric substances and waxes.

Dosage forms for topical and/or transdermal administration of a compounddescribed herein may include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants, and/or patches. Generally, theactive ingredient is admixed under sterile conditions with apharmaceutically acceptable carrier or excipient and/or any neededpreservatives and/or buffers as can be required. Additionally, thepresent disclosure contemplates the use of transdermal patches, whichoften have the added advantage of providing controlled delivery of anactive ingredient to the body. Such dosage forms can be prepared, forexample, by dissolving and/or dispensing the active ingredient in theproper medium. Alternatively or additionally, the rate can be controlledby either providing a rate controlling membrane and/or by dispersing theactive ingredient in a polymer matrix and/or gel.

Suitable devices for use in delivering intradermal pharmaceuticalcompositions described herein include short needle devices. Intradermalcompositions can be administered by devices which limit the effectivepenetration length of a needle into the skin. Alternatively oradditionally, conventional syringes can be used in the classical mantouxmethod of intradermal administration. Jet injection devices whichdeliver liquid formulations to the dermis via a liquid jet injectorand/or via a needle which pierces the stratum corneum and produces a jetwhich reaches the dermis are suitable. Ballistic powder/particledelivery devices which use compressed gas to accelerate the compound inpowder form through the outer layers of the skin to the dermis aresuitable.

Formulations suitable for topical administration include, but are notlimited to, liquid and/or semi-liquid preparations such as liniments,lotions, oil-in-water and/or water-in-oil emulsions such as creams,ointments, and/or pastes, and/or solutions and/or suspensions. Topicallyadministrable formulations may, for example, comprise from about 1% toabout 10% (w/w) active ingredient, although the concentration of theactive ingredient can be as high as the solubility limit of the activeingredient in the solvent. Formulations for topical administration mayfurther comprise one or more of the additional ingredients describedherein.

A pharmaceutical composition described herein can be prepared, packaged,and/or sold in a formulation suitable for pulmonary administration viathe buccal cavity. Such a formulation may comprise dry particles whichcomprise the active ingredient and which have a diameter in the rangefrom about 0.5 to about 7 nanometers, or from about 1 to about 6nanometers. Such compositions are conveniently in the form of drypowders for administration using a device comprising a dry powderreservoir to which a stream of propellant can be directed to dispersethe powder and/or using a self-propelling solvent/powder dispensingcontainer such as a device comprising the active ingredient dissolvedand/or suspended in a low-boiling propellant in a sealed container. Suchpowders comprise particles wherein at least 98% of the particles byweight have a diameter greater than 0.5 nanometers and at least 95% ofthe particles by number have a diameter less than 7 nanometers.Alternatively, at least 95% of the particles by weight have a diametergreater than 1 nanometer and at least 90% of the particles by numberhave a diameter less than 6 nanometers. Dry powder compositions mayinclude a solid fine powder diluent such as sugar and are convenientlyprovided in a unit dose form.

Low boiling propellants generally include liquid propellants having aboiling point of below 65° F. at atmospheric pressure. Generally thepropellant may constitute 50 to 99.9% (w/w) of the composition, and theactive ingredient may constitute 0.1 to 20% (w/w) of the composition.The propellant may further comprise additional ingredients such as aliquid non-ionic and/or solid anionic surfactant and/or a solid diluent(which may have a particle size of the same order as particlescomprising the active ingredient).

Pharmaceutical compositions described herein formulated for pulmonarydelivery may provide the active ingredient in the form of droplets of asolution and/or suspension. Such formulations can be prepared, packaged,and/or sold as aqueous and/or dilute alcoholic solutions and/orsuspensions, optionally sterile, comprising the active ingredient, andmay conveniently be administered using any nebulization and/oratomization device. Such formulations may further comprise one or moreadditional ingredients including, but not limited to, a flavoring agentsuch as saccharin sodium, a volatile oil, a buffering agent, a surfaceactive agent, and/or a preservative such as methylhydroxybenzoate. Thedroplets provided by this route of administration may have an averagediameter in the range from about 0.1 to about 200 nanometers.

Formulations described herein as being useful for pulmonary delivery areuseful for intranasal delivery of a pharmaceutical composition describedherein. Another formulation suitable for intranasal administration is acoarse powder comprising the active ingredient and having an averageparticle from about 0.2 to 500 micrometers. Such a formulation isadministered by rapid inhalation through the nasal passage from acontainer of the powder held close to the nares.

Formulations for nasal administration may, for example, comprise fromabout as little as 0.1% (w/w) to as much as 100% (w/w) of the activeingredient, and may comprise one or more of the additional ingredientsdescribed herein. A pharmaceutical composition described herein can beprepared, packaged, and/or sold in a formulation for buccaladministration. Such formulations may, for example, be in the form oftablets and/or lozenges made using conventional methods, and maycontain, for example, 0.1 to 20% (w/w) active ingredient, the balancecomprising an orally dissolvable and/or degradable composition and,optionally, one or more of the additional ingredients described herein.Alternately, formulations for buccal administration may comprise apowder and/or an aerosolized and/or atomized solution and/or suspensioncomprising the active ingredient. Such powdered, aerosolized, and/oraerosolized formulations, when dispersed, may have an average particleand/or droplet size in the range from about 0.1 to about 200 nanometers,and may further comprise one or more of the additional ingredientsdescribed herein.

A pharmaceutical composition described herein can be prepared, packaged,and/or sold in a formulation for ophthalmic administration. Suchformulations may, for example, be in the form of eye drops including,for example, a 0.1-1.0% (w/w) solution and/or suspension of the activeingredient in an aqueous or oily liquid carrier or excipient. Such dropsmay further comprise buffering agents, salts, and/or one or more otherof the additional ingredients described herein. Otheropthalmically-administrable formulations which are useful include thosewhich comprise the active ingredient in microcrystalline form and/or ina liposomal preparation. Ear drops and/or eye drops are alsocontemplated as being within the scope of this disclosure.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, such compositions are generallysuitable for administration to animals of all sorts. Modification ofpharmaceutical compositions suitable for administration to humans inorder to render the compositions suitable for administration to variousanimals is well understood, and the ordinarily skilled veterinarypharmacologist can design and/or perform such modification with ordinaryexperimentation.

The compounds provided herein are typically formulated in dosage unitform for ease of administration and uniformity of dosage. It will beunderstood, however, that the total daily usage of the compositionsdescribed herein will be decided by a physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular subject or organism will depend upon a varietyof factors including the disease being treated and the severity of thedisorder; the activity of the specific active ingredient employed; thespecific composition employed; the age, body weight, general health,sex, and diet of the subject; the time of administration, route ofadministration, and rate of excretion of the specific active ingredientemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific active ingredient employed; and likefactors well known in the medical arts.

The compounds and compositions provided herein can be administered byany route, including enteral (e.g., oral), parenteral, intravenous,intramuscular, intra-arterial, intramedullary, intrathecal,subcutaneous, intraventricular, transdermal, interdermal, rectal,intravaginal, intraperitoneal, topical (as by powders, ointments,creams, and/or drops), mucosal, nasal, bucal, sublingual; byintratracheal instillation, bronchial instillation, and/or inhalation;and/or as an oral spray, nasal spray, and/or aerosol. Specificallycontemplated routes are oral administration, intravenous administration(e.g., systemic intravenous injection), regional administration viablood and/or lymph supply, and/or direct administration to an affectedsite. In general, the most appropriate route of administration willdepend upon a variety of factors including the nature of the agent(e.g., its stability in the environment of the gastrointestinal tract),and/or the condition of the subject (e.g., whether the subject is ableto tolerate oral administration). In certain embodiments, the compoundor pharmaceutical composition described herein is suitable for topicaladministration to the eye of a subject.

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular compound, mode of administration,and the like. An effective amount may be included in a single dose(e.g., single oral dose) or multiple doses (e.g., multiple oral doses).In certain embodiments, when multiple doses are administered to asubject or applied to a biological sample, tissue, or cell, any twodoses of the multiple doses include different or substantially the sameamounts of a compound described herein. In certain embodiments, whenmultiple doses are administered to a subject or applied to a biologicalsample, tissue, or cell, the frequency of administering the multipledoses to the subject or applying the multiple doses to the tissue orcell is three doses a day, two doses a day, one dose a day, one doseevery other day, one dose every third day, one dose every week, one doseevery two weeks, one dose every three weeks, or one dose every fourweeks. In certain embodiments, the frequency of administering themultiple doses to the subject or applying the multiple doses to thetissue or cell is one dose per day. In certain embodiments, thefrequency of administering the multiple doses to the subject or applyingthe multiple doses to the tissue or cell is two doses per day. Incertain embodiments, the frequency of administering the multiple dosesto the subject or applying the multiple doses to the tissue or cell isthree doses per day. In certain embodiments, when multiple doses areadministered to a subject or applied to a biological sample, tissue, orcell, the duration between the first dose and last dose of the multipledoses is one day, two days, four days, one week, two weeks, three weeks,one month, two months, three months, four months, six months, ninemonths, one year, two years, three years, four years, five years, sevenyears, ten years, fifteen years, twenty years, or the lifetime of thesubject, biological sample, tissue, or cell. In certain embodiments, theduration between the first dose and last dose of the multiple doses isthree months, six months, or one year. In certain embodiments, theduration between the first dose and last dose of the multiple doses isthe lifetime of the subject, biological sample, tissue, or cell. Incertain embodiments, a dose (e.g., a single dose, or any dose ofmultiple doses) described herein includes independently between 0.1 μgand 1 μg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg,between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg,between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive,of a compound described herein. In certain embodiments, a dose describedherein includes independently between 1 mg and 3 mg, inclusive, of acompound described herein. In certain embodiments, a dose describedherein includes independently between 3 mg and 10 mg, inclusive, of acompound described herein. In certain embodiments, a dose describedherein includes independently between 10 mg and 30 mg, inclusive, of acompound described herein. In certain embodiments, a dose describedherein includes independently between 30 mg and 100 mg, inclusive, of acompound described herein.

Dose ranges as described herein provide guidance for the administrationof provided pharmaceutical compositions to an adult. The amount to beadministered to, for example, a child or an adolescent can be determinedby a medical practitioner or person skilled in the art and can be loweror the same as that administered to an adult.

A compound or composition, as described herein, can be administered incombination with one or more additional pharmaceutical agents (e.g.,therapeutically and/or prophylactically active agents) useful intreating and/or preventing a proliferative disease. The compounds orcompositions can be administered in combination with additionalpharmaceutical agents that improve their activity (e.g., activity (e.g.,potency and/or efficacy) in treating a proliferative disease in asubject in need thereof, in preventing a proliferative disease in asubject in need thereof, and/or in inhibiting the activity of a proteinkinase (e.g., HCK, BTK) in a subject, biological sample, tissue, orcell), improve bioavailability, improve safety, reduce drug resistance,reduce and/or modify metabolism, inhibit excretion, and/or modifydistribution in a subject, biological sample, tissue, or cell. It willalso be appreciated that the therapy employed may achieve a desiredeffect for the same disorder, and/or it may achieve different effects.In certain embodiments, a pharmaceutical composition described hereinincluding a compound described herein and an additional pharmaceuticalagent shows a synergistic effect that is absent in a pharmaceuticalcomposition including one of the compound and the additionalpharmaceutical agent, but not both.

The compound or composition can be administered concurrently with, priorto, or subsequent to one or more additional pharmaceutical agents, whichmay be useful as, e.g., combination therapies in treating and/orpreventing a proliferative disease. Pharmaceutical agents includetherapeutically active agents. Pharmaceutical agents also includeprophylactically active agents. Pharmaceutical agents include smallorganic molecules such as drug compounds (e.g., compounds approved forhuman or veterinary use by the U.S. Food and Drug Administration asprovided in the Code of Federal Regulations (CFR)), peptides, proteins,carbohydrates, monosaccharides, oligosaccharides, polysaccharides,nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides orproteins, small molecules linked to proteins, glycoproteins, steroids,nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides,antisense oligonucleotides, lipids, hormones, vitamins, and cells. Incertain embodiments, the additional pharmaceutical agent is apharmaceutical agent useful in treating a proliferative disease. Incertain embodiments, the additional pharmaceutical agent is apharmaceutical agent useful in preventing a proliferative disease. Incertain embodiments, the additional pharmaceutical agent is apharmaceutical agent useful in inhibiting the activity of a proteinkinase (e.g., HCK, BTK) in a subject, biological sample, tissue, orcell. In certain embodiments, the additional pharmaceutical agent is apharmaceutical agent useful in inducing apoptosis in a cell. In certainembodiments, the additional pharmaceutical agent is a pharmaceuticalagent approved by a regulatory agency (e.g., the US FDA) for treatingand/or preventing a proliferative disease. Each additionalpharmaceutical agent may be administered at a dose and/or on a timeschedule determined for that pharmaceutical agent. The additionalpharmaceutical agents may also be administered together with each otherand/or with the compound or composition described herein in a singledose or administered separately in different doses. The particularcombination to employ in a regimen will take into account compatibilityof the compound described herein with the additional pharmaceuticalagent(s) and/or the desired therapeutic and/or prophylactic effect to beachieved. In general, it is expected that the additional pharmaceuticalagent(s) in combination be utilized at levels that do not exceed thelevels at which they are utilized individually. In some embodiments, thelevels utilized in combination will be lower than those utilizedindividually.

In certain embodiments, the additional pharmaceutical agent is ananti-proliferative agent (e.g., anti-cancer agent). In certainembodiments, the additional pharmaceutical agent is an anti-leukemiaagent. In certain embodiments, the additional pharmaceutical agent isABITREXATE (methotrexate), ADE, Adriamycin RDF (doxorubicinhydrochloride), Ambochlorin (chlorambucil), ARRANON (nelarabine),ARZERRA (ofatumumab), BOSULIF (bosutinib), BUSULFEX (busulfan), CAMPATH(alemtuzumab), CERUBIDINE (daunorubicin hydrochloride), CLAFEN(cyclophosphamide), CLOFAREX (clofarabine), CLOLAR (clofarabine), CVP,CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), ERWINAZE(Asparaginase Erwinia Chrysanthemi), FLUDARA (fludarabine phosphate),FOLEX (methotrexate), FOLEX PFS (methotrexate), GAZYVA (obinutuzumab),GLEEVEC (imatinib mesylate), Hyper-CVAD, ICLUSIG (ponatinibhydrochloride), IMBRUVICA (ibrutinib), LEUKERAN (chlorambucil),LINFOLIZIN (chlorambucil), MARQIBO (vincristine sulfate liposome),METHOTREXATE LPF (methorexate), MEXATE (methotrexate), MEXATE-AQ(methotrexate), mitoxantrone hydrochloride, MUSTARGEN (mechlorethaminehydrochloride), MYLERAN (busulfan), NEOSAR (cyclophosphamide), ONCASPAR(Pegaspargase), PURINETHOL (mercaptopurine), PURIXAN (mercaptopurine),Rubidomycin (daunorubicin hydrochloride), SPRYCEL (dasatinib), SYNRIBO(omacetaxine mepesuccinate), TARABINE PFS (cytarabine), TASIGNA(nilotinib), TREANDA (bendamustine hydrochloride), TRISENOX (arsenictrioxide), VINCASAR PFS (vincristine sulfate), ZYDELIG (idelalisib), ora combination thereof. In certain embodiments, the additionalpharmaceutical agent is an anti-lymphoma agent. In certain embodiments,the additional pharmaceutical agent is ABITREXATE (methotrexate), ABVD,ABVE, ABVE-PC, ADCETRIS (brentuximab vedotin), ADRIAMYCIN PFS(doxorubicin hydrochloride), ADRIAMYCIN RDF (doxorubicin hydrochloride),AMBOCHLORIN (chlorambucil), AMBOCLORIN (chlorambucil), ARRANON(nelarabine), BEACOPP, BECENUM (carmustine), BELEODAQ (belinostat),BEXXAR (tositumomab and iodine I 131 tositumomab), BICNU (carmustine),BLENOXANE (bleomycin), CARMUBRIS (carmustine), CHOP, CLAFEN(cyclophosphamide), COPP, COPP-ABV, CVP, CYTOXAN (cyclophosphamide),DEPOCYT (liposomal cytarabine), DTIC-DOME (dacarbazine), EPOCH, FOLEX(methotrexate), FOLEX PFS (methotrexate), FOLOTYN (pralatrexate),HYPER-CVAD, ICE, IMBRUVICA (ibrutinib), INTRON A (recombinant interferonalfa-2b), ISTODAX (romidepsin), LEUKERAN (chlorambucil), LINFOLIZIN(chlorambucil), Lomustine, MATULANE (procarbazine hydrochloride),METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ(methotrexate), MOPP, MOZOBIL (plerixafor), MUSTARGEN (mechlorethaminehydrochloride), NEOSAR (cyclophosphamide), OEPA, ONTAK (denileukindiftitox), OPPA, R—CHOP, REVLIMID (lenalidomide), RITUXAN (rituximab),STANFORD V, TREANDA (bendamustine hydrochloride), VAMP, VELBAN(vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastinesulfate), VINCASAR PFS (vincristine sulfate), ZEVALIN (ibritumomabtiuxetan), ZOLINZA (vorinostat), ZYDELIG (idelalisib), or a combinationthereof. In certain embodiments, the additional pharmaceutical agent isan anti-myelodysplasia agent. In certain embodiments, the additionalpharmaceutical agent is REVLIMID (lenalidomide), DACOGEN (decitabine),VIDAZA (azacitidine), CYTOSAR-U (cytarabine), IDAMYCIN (idarubicin),CERUBIDINE (daunorubicin), or a combination thereof.

In certain embodiments, the additional pharmaceutical agent is ananti-macroglobulinemia agent.In certain embodiments, the additional pharmaceutical agent is LEUKERAN(chlorambucil), NEOSAR (cyclophosphamide), FLUDARA (fludarabine),LEUSTATIN (cladribine), or a combination thereof. In certainembodiments, the additional pharmaceutical agent is ABITREXATE(methotrexate), ABRAXANE (paclitaxel albumin-stabilized nanoparticleformulation), AC, AC-T, ADE, ADRIAMYCIN PFS (doxorubicin hydrochloride),ADRUCIL (fluorouracil), AFINITOR (everolimus), AFINITOR DISPERZ(everolimus), ALDARA (imiquimod), ALIMTA (pemetrexed disodium), AREDIA(pamidronate disodium), ARIMIDEX (anastrozole), AROMASIN (exemestane),AVASTIN (bevacizumab), BECENUM (carmustine), BEP, BICNU (carmustine),BLENOXANE (bleomycin), CAF, CAMPTOSAR (irinotecan hydrochloride), CAPOX,CAPRELSA (vandetanib), CARBOPLATIN-TAXOL, CARMUBRIS (carmustine),CASODEX (bicalutamide), CEENU (lomustine), CERUBIDINE (daunorubicinhydrochloride), CERVARIX (recombinant HPV bivalent vaccine), CLAFEN(cyclophosphamide), CMF, COMETRIQ (cabozantinib-s-malate), COSMEGEN(dactinomycin), CYFOS (ifosfamide), CYRAMZA (ramucirumab), CYTOSAR-U(cytarabine), CYTOXAN (cyclophosphamide), DACOGEN (decitabine),DEGARELIX, DOXIL (doxorubicin hydrochloride liposome), DOXORUBICINHYDROCHLORIDE, DOX-SL (doxorubicin hydrochloride liposome), DTIC-DOME(dacarbazine), EFUDEX (fluorouracil), ELLENCE (epirubicinhydrochloride), ELOXATIN (oxaliplatin), ERBITUX (cetuximab), ERIVEDGE(vismodegib), ETOPOPHOS (etoposide phosphate), EVACET (doxorubicinhydrochloride liposome), FARESTON (toremifene), FASLODEX (fulvestrant),FEC, FEMARA (letrozole), FLUOROPLEX (fluorouracil), FOLEX(methotrexate), FOLEX PFS (methotrexate), FOLFIRI, FOLFIRI-BEVACIZUMAB,FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, FU-LV, GARDASIL (recombinanthuman papillomavirus (HPV) quadrivalent vaccine), GEMCITABINE-CISPLATIN,GEMCITABINE-OXALIPLATIN, GEMZAR (gemcitabine hydrochloride), GILOTRIF(afatinib dimaleate), GLEEVEC (imatinib mesylate), GLIADEL (carmustineimplant), GLIADEL WAFER (carmustine implant), HERCEPTIN (trastuzumab),HYCAMTIN (topotecan hydrochloride), IFEX (ifosfamide), IFOSFAMIDUM(ifosfamide), INLYTA (axitinib), INTRON A (recombinant interferonalfa-2b), IRESSA (gefitinib), IXEMPRA (ixabepilone), JAKAFI (ruxolitinibphosphate), JEVTANA (cabazitaxel), KADCYLA (ado-trastuzumab emtansine),KEYTRUDA (pembrolizumab), KYPROLIS (carfilzomib), LIPODOX (doxorubicinhydrochloride liposome), LUPRON (leuprolide acetate), LUPRON DEPOT(leuprolide acetate), LUPRON DEPOT-3 MONTH (leuprolide acetate), LUPRONDEPOT-4 MONTH (leuprolide acetate), LUPRON DEPOT-PED (leuprolideacetate), MEGACE (megestrol acetate), MEKINIST (trametinib),METHAZOLASTONE (temozolomide), METHOTREXATE LPF (methotrexate), MEXATE(methotrexate), MEXATE-AQ (methotrexate), MITOXANTRONE HYDROCHLORIDE,MITOZYTREX (mitomycin c), MOZOBIL (plerixafor), MUSTARGEN(mechlorethamine hydrochloride), MUTAMYCIN (mitomycin c), MYLOSAR(azacitidine), NAVELBINE (vinorelbine tartrate), NEOSAR(cyclophosphamide), NEXAVAR (sorafenib tosylate), NOLVADEX (tamoxifencitrate), NOVALDEX (tamoxifen citrate), OFF, PAD, PARAPLAT(carboplatin), PARAPLATIN (carboplatin), PEG-INTRON (peginterferonalfa-2b), PEMETREXED DISODIUM, PERJETA (pertuzumab), PLATINOL(cisplatin), PLATINOL-AQ (cisplatin), POMALYST (pomalidomide),prednisone, PROLEUKIN (aldesleukin), PROLIA (denosumab), PROVENGE(sipuleucel-t), REVLIMID (lenalidomide), RUBIDOMYCIN (daunorubicinhydrochloride), SPRYCEL (dasatinib), STIVARGA (regorafenib), SUTENT(sunitinib malate), SYLATRON (peginterferon alfa-2b), SYLVANT(siltuximab), SYNOVIR (thalidomide), TAC, TAFINLAR (dabrafenib),TARABINE PFS (cytarabine), TARCEVA (erlotinib hydrochloride), TASIGNA(nilotinib), TAXOL (paclitaxel), TAXOTERE (docetaxel), TEMODAR(temozolomide), THALOMID (thalidomide), TOPOSAR (etoposide), TORISEL(temsirolimus), TPF, TRISENOX (arsenic trioxide), TYKERB (lapatinibditosylate), VECTIBIX (panitumumab), VEIP, VELBAN (vinblastine sulfate),VELCADE (bortezomib), VELSAR (vinblastine sulfate), VEPESID (etoposide),VIADUR (leuprolide acetate), VIDAZA (azacitidine), VINCASAR PFS(vincristine sulfate), VOTRIENT (pazopanib hydrochloride), WELLCOVORIN(leucovorin calcium), XALKORI (crizotinib), XELODA (capecitabine),XELOX, XGEVA (denosumab), XOFIGO (radium 223 dichloride), XTANDI(enzalutamide), YERVOY (ipilimumab), ZALTRAP (ziv-aflibercept), ZELBORAF(vemurafenib), ZOLADEX (goserelin acetate), ZOMETA (zoledronic acid),ZYKADIA (ceritinib), ZYTIGA (abiraterone acetate), or a combinationthereof. In certain embodiments, the additional pharmaceutical agent isa protein kinase inhibitor (e.g., tyrosine protein kinase inhibitor). Incertain embodiments, the additional pharmaceutical agent is an inhibitorof a Src family kinase. In certain embodiments, the additionalpharmaceutical agent is an HCK inhibitor or BTK inhibitor. In certainembodiments, the additional pharmaceutical agent is an inhibitor of oneor more protein kinases selected from the group consisting of IRAK1,IRAK4, BMX, and PI3K. In certain embodiments, the additionalpharmaceutical agent is an inhibitor of one or more protein kinasesselected from the group consisting of ABL, ACK, ARG, BLK, CSK, EphB1,EphB2, FGR, FRK, FYN, SRC, YES, LCK, LYN, MAP2K5, NLK, PIP4K2C, p38a,SNRK, SRC, and TEC. In certain embodiments, the additionalpharmaceutical agent is an inhibitor of one or more protein kinasesselected from the group consisting of ABL1(H396P)-phosphorylated,ABL-phosphorylated, BLK, EPHA4, EPHB2, EPHB3, EPHB4, FGR,JAK3(JH1domain-catalytic), KIT, KIT(L576P), KIT(V559D), PDGFRB, SRC,YES, ABL1(H396P)-nonphosphorylated, ABL1(Y253F)-phosphorylated,ABL1-nonphosphorylated, FRK, LYN, ABL1(Q252H)-nonphosphorylated, DDR1,EPHB1, ERBB4, p38-alpha, ABL2, ABL1(Q252H)-phosphorylated, SIK, EPHA8,MEK5, ABL1(E255K)-phosphorylated, AB L(F317L)-nonphosphorylated, FYN,LCK, EPHA2, ABL(M351T)-phosphorylated, TXK, EGFR(L858R), EGFR(L861Q),ERBB2, ERBB3, EPHA5, ABL1(F317I)-nonphosphorylated, EGFR(L747-E749del,A750P), CSK, EPHA1, ABL1(F317L)-phosphorylated, BRAF(V600E), EGFR,KIT-autoinhibited, and EGFR(E746-A750del). In certain embodiments, theadditional pharmaceutical agent is an inhibitor of one or more proteinkinases selected from the group consisting ofABL1(F317L)-nonphosphorylated, AB L (H396P)-nonphosphorylated, AB L(H396P)-phosphorylated, ABL-phosphorylated, BLK, EPHA4, EPHB2, EPHB3,EPHB4, JAK3(JH1domain-catalytic), KIT, KIT(L576P), KIT(V559D), LYN,PDGFRB, SRC, YES, ABL1-nonphosphorylated, ABL1(Y253F)-phosphorylated,ERBB3, FGR, FRK, p38-alpha, ABL1(F317I)-nonphosphorylated, DDR1, EPHA2,ABL1(Q252H)-phosphorylated, MEK5, ABL1(Q252H)-nonphosphorylated, ABL2,FYN, EPHB1, ABL1(E255K)-phosphorylated, ABL1(F317L)-phosphorylated,EPHA1, ABL1(M351T)-phosphorylated, ERBB4, TXK, LCK, EPHA8, SIK, EPHA5,EGFR(L861Q), CSF1R-autoinhibited, BRAF(V600E), BRK, CSK, KIT(D816V),KIT-autoinhibited, EGFR(L747-T751del,Sins), EGFR(L858R),EGFR(L747-E749del, A750P), and CSF1R. In certain embodiments, theadditional pharmaceutical agent is an anti-angiogenesis agent,anti-inflammatory agent, immunosuppressant, anti-bacterial agent,anti-viral agent, cardiovascular agent, cholesterol-lowering agent,anti-diabetic agent, anti-allergic agent, pain-relieving agent, or acombination thereof. In certain embodiments, the compounds describedherein or pharmaceutical compositions can be administered in combinationwith an anti-cancer therapy including, but not limited to,transplantation (e.g., bone marrow transplantation, stem celltransplantation), surgery, radiation therapy, immunotherapy, andchemotherapy.

Also encompassed by the disclosure are kits (e.g., pharmaceuticalpacks). The kits provided may comprise a pharmaceutical composition orcompound described herein and a container (e.g., a vial, ampule, bottle,syringe, and/or dispenser package, or other suitable container). In someembodiments, provided kits may optionally further include a secondcontainer comprising a pharmaceutical excipient for dilution orsuspension of a pharmaceutical composition or compound described herein.In some embodiments, the pharmaceutical composition or compounddescribed herein provided in the first container and the secondcontainer are combined to form one unit dosage form.

In certain embodiments, a kit described herein includes a firstcontainer comprising a compound or pharmaceutical composition describedherein. In certain embodiments, a kit described herein is useful intreating a proliferative disease (e.g., myelodysplasia, leukemia,lymphoma (e.g., Waldenström's macroglobulinemia)) in a subject in needthereof, preventing a proliferative disease in a subject in needthereof, inhibiting the activity of a protein kinase (e.g., HCK, BTK) ina subject, biological sample, tissue, or cell, and/or inducing apoptosisin a cell.

In certain embodiments, a kit described herein further includesinstructions for using the compound or pharmaceutical compositionincluded in the kit. A kit described herein may also include informationas required by a regulatory agency such as the U.S. Food and DrugAdministration (FDA). In certain embodiments, the information includedin the kits is prescribing information. In certain embodiments, the kitsand instructions provide for treating a proliferative disease in asubject in need thereof, preventing a proliferative disease in a subjectin need thereof, inhibiting the activity of a protein kinase (e.g., HCK,BTK) in a subject, biological sample, tissue, or cell, and/or inducingapoptosis in a cell. A kit described herein may include one or moreadditional pharmaceutical agents described herein as a separatecomposition.

Methods of Treatment

The compounds described herein may:

-   -   exhibit kinase inhibitory activity,    -   exhibit the ability to inhibit transforming growth factor        b-activated kinase-1 (TAK1), hemopoietic cell kinase (HCK) or        both TAK1 and HCK,    -   exhibit the ability to inhibit Bruton's tyrosine kinase (BTK),        v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (SRC)        family of kinases or both BTK and SRC,    -   exhibit cytotoxic or growth inhibitory effect on Waldenström's        macroglobulinemia (WM) cell lines maintained in vitro or in        animal studies using a scientifically acceptable cancer cell        xenograft model; and/or    -   exhibit a therapeutic profile (e.g., optimum safety and curative        effect) that is superior to existing chemotherapeutic agents.

Without wishing to be bound by any particular theory, the compoundsdescribed herein may be able to attach (e.g., covalently attach) to aprotein kinase described herein. In certain embodiments, the R^(A10),R^(B9), or R^(C9) group of a compound described herein is able to attach(e.g., covalently attach) to the protein kinase.

In another aspect, the present disclosure provides methods of inhibitingthe activity of a protein kinase in a subject, the methods comprisingadministering to the subject an effective amount (e.g., therapeuticallyeffective amount) of a compound or pharmaceutical composition describedherein.

In another aspect, the present disclosure provides methods of inhibitingthe activity of a protein kinase in a biological sample, the methodscomprising contacting the biological sample with an effective amount ofa compound or pharmaceutical composition described herein.

In another aspect, the present disclosure provides methods of inhibitingthe activity of a protein kinase in a tissue, the methods comprisingcontacting the tissue with an effective amount of a compound orpharmaceutical composition described herein.

In another aspect, the present disclosure provides methods of inhibitingthe activity of a protein kinase in a cell, the methods comprisingcontacting the cell with an effective amount of a compound orpharmaceutical composition described herein.

In some embodiments, the protein kinase is involved in the myeloiddifferentiation primary response gene (88) (MYD88) signaling pathway. Incertain embodiments, the protein kinase is a Src family kinase, such ashemopoietic cell kinase (HCK). In certain embodiments, the proteinkinase is Bruton's tyrosine kinase (BTK). In certain embodiments, theprotein kinase is IRAK1, IRAK4, BMX, or a PI3K.

MYD88 is an adaptor molecule for Toll-like receptors (TLR) with theexception of TLR-3 and interleukin-1 receptor (IL-1R) signaling.Following TLR or IL-1R stimulation, MYD88 is recruited to the activatedreceptor complex as a homodimer which then complexes with interleukin-1receptor-associated kinase 4 (IRAK4) and activates IRAK1 and IRAK2.Tumor necrosis factor receptor associated factor 6 (TRAF6) is thenactivated by IRAK1 leading to NFκB activation via IκBα phosphorylation.

Transforming growth factor b-activated kinase-1 (TAK1; also known asMAP3K7), is a member of the serine/threonine protein kinase family. Thiskinase mediates the signaling transduction induced by TGF beta andmorphogenetic protein (BMP), and controls a variety of cell functionsincluding transcription regulation and apoptosis. TAK1 knockout isembryonic lethal to mice. Conditional knock-down of TAK1 in adult miceresults in systemic inflammation, spenomegaly, degeneration in heart,kidneys and liver and increased proliferation and differentiation ofmyeloid progenitor cells. TAK1 is located downstream of Myd88, Bruton'styrosine kinase (BTK) and interleukin-1 receptor-associated kinase(IRAK), and is being investigated for its role in innate immunity,inflammatory response and Ras dependent cancers.

HCK is a non-receptor tyrosine-protein kinase found in hematopoieticcells and is known to interact with Bruton's tyrosine kinase (BTK) uponactivation by B cell receptors (Proc Natl Acad Sci USA. 1994 Aug. 16;91(17): 8152-8155). HCK transmits signals from cell surface receptorsand plays an important role in the regulation of innate immuneresponses, including neutrophil, monocyte, macrophage and mast cellfunctions, phagocytosis, cell survival and proliferation, cell adhesionand migration. It acts downstream of receptors that bind the Fc regionof immunoglobulins, such as FCGR1A and FCGR2A, but also CSF3R, PLAUR,the receptors for IFNG, IL2, IL6 and IL8, and integrins, such as ITGB1and ITGB2. During the phagocytic process, it mediates mobilization ofsecretory lysosomes, degranulation, and activation of NADPH oxidase tobring about the respiratory burst. It also plays a role in the releaseof inflammatory molecules, promotes reorganization of the actincytoskeleton and actin polymerization, and formation of podosomes andcell protrusions.

BTK is a key signaling enzyme expressed in all hematopoietic cells typesexcept T lymphocytes and natural killer cells. BTK plays an essentialrole in the B cell signaling pathway linking cell surface B cellreceptor BCR stimulation to downstream intracellular responses. BTK is akey regulator of B cell development activation signaling and survival(Kurosaki, Curr. Op. Imm., 2000, 276-281; Schaeffer and Schwartzberg,Curr. Op. Imm., 2000, 282-288). In addition BTK plays a role in a numberof other hematopoietic cell signaling pathways, e.g., Toll like receptor(TLR) and cytokine receptor-mediated TNF-α production in macrophages,IgE receptor (FcepsilonRI) signaling in mast cells, inhibition ofFas/APO-1 apoptotic signaling in B-lineage lymphoid cells, and collagenstimulated platelet aggregation. See e.g., C. A. Jeffries, et al., J.Biol. Chem., 2003, 278, 26258-26264; N. J. Horwood, et al., J. Exp.Med., 2003, 197, 1603-1611; Iwaki et al., J. Biol. Chem., 2005, 280(48),40261-40270; Vassilev et al., J. Biol. Chem., 1999, 274(3),1646-1656;and Quek et al., Curr. Biol., 1998, 8(20),1137-1140. Activated Btkinteracts with MyD88 and TRIF, promoting the activation ofMyD88-dependent and TRIF-dependent pathways (Nature Immunology, 2011,12, 416-424). BTK inhibitors are well-known in the art, and include, forexample, ibrutinib and benzonaphthyridinones (see U.S. provisionalpatent application U.S. Ser. No. 61/716,273, filed Oct. 19, 2012).Additional non-limiting examples of BTK inhibitors are disclosed in WO1999/054286, WO 2013/010380, WO 2009/137596, WO 2011/029043, WO2010/056875, WO 2000/056737, and WO 2013/067277.

IRAK1 and IRAK4 are serine/threonine-protein kinases that play acritical role in initiating innate immune response against foreignpathogens. They are involved in Toll-like receptor (TLR) and IL-1Rsignaling pathways, and are rapidly recruited by MYD88 to thereceptor-signaling complex upon TLR activation. Association with MYD88leads to IRAK1 phosphorylation by IRAK4 and subsequentautophosphorylation and kinase activation of IRAK1 (Immunity, 1997,7(6), 837-47). IRAK4−/− mice have abolished cellular responses tovarious IL-1 and TLR ligands and are severely impaired in their responseto viral and bacterial challenges. IRAK1−/− mice show a similar butpartial response. IRAK1 and IRAK4 inhibitors are well-known in the art,and include, for example, those disclosed in WO 2003/030902, WO2012/007375, GM Buckely et al. Biorg. Med. Chem. Lett. 2008 183211-3214, and GM Buckely et al. Biorg. Med. Chem. Lett. 2008 183656-3660, WO2013/074986, and U.S. 61/727,640.

“Bone Marrow on X chromosome” kinase (BMX, also termed ETK) is anon-receptor tyrosine kinase and is activated downstream ofphosphatidylinositol-3 kinase (PI-3K) and v-src sarcoma (Schmidt-RuppinA-2) viral oncogene homolog (SRC), but its substrates are unknown.Positional scanning peptide library screening revealed a markedpreference for a priming phosphotyrosine (pY) in the −1 position.Potential substrates include multiple tyrosine kinases with kinasedomain pYpY sites required for full activity. BMX has been found tophosphorylate residue Y577 of focal adhesion kinase (FAK) subsequent toY576 phosphorylation by SRC. In addition, BMX loss by RNA interferenceand mouse embryonic fibroblasts (MEFs) from Bmx negative (Bmx⁻) micedisplayed impaired FAK signaling. Insulin receptor (IR) phosphorylationsimilarly was decreased by BMX loss, as was hepatic IR phosphorylationin Bmx⁻ mice. However, glucose tolerance was increased, reflecting amarked compensatory decrease in the activity of the AKT phosphatasePHLPP. These findings reveal a mechanism through which BMX functions asa central regulator of multiple kinase pathways. BMX inhibitors arewell-known in the art, and include, for example, those disclosed in U.S.Ser. No. 61/716,273 and 61/717,345, the contents of both of which areincorporated herein by reference.

Phosphatidylinositol 3-kinases (PI3-kinases or PI3Ks) are a family ofenzymes involved in cellular functions such as cell growth,proliferation, differentiation, motility, survival and intracellulartrafficking, which in turn are involved in cancer. PI3Ks are a family ofrelated intracellular signal transducer enzymes capable ofphosphorylating the 3 position hydroxyl group of the inositol ring ofphosphatidylinositol (Ptdlns). Phosphatidylinositol 3-kinase is composedof an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. Theprotein encoded by PI3KCA gene represents the catalytic subunit, whichuses ATP to phosphorylate phosphatidylinositols (Ptdlns), Ptdlns4P andPtdlns(4,5)P2. PI3K inhibitors are well-known in the art, and include,for example, those disclosed in WO 2013/088404, WO 2012/068096, and WO2013/052699, which are incorporated herein by reference. In certainembodiments, the activity of the protein kinase is inhibited by thecompounds or pharmaceutical compositions described herein by at least10%, at least 20%, at least 30%, at least 40%, at least 50%, at least60%, at least 70%, at least 80%, at least 90%, or at least 95%. Incertain embodiments, the activity of the protein kinase is inhibited bythe compounds or pharmaceutical compositions described herein by notmore than 90%, not more than 80%, not more than 70%, not more than 60%,not more than 50%, not more than 40%, not more than 30%, not more than20%, or not more than 10%. Combinations of the above-referenced ranges(e.g., at least 10% and not more than 50%) are also within the scope ofthe disclosure.

In some embodiments, the activity of a protein kinase described hereinis selectively inhibited by the compounds or pharmaceutical compositionsdescribed herein, compared to the activity of a different protein (e.g.,a different protein kinase). In certain embodiments, the activity of aSrc family kinase (e.g., HCK) is selectively inhibited by a compound orpharmaceutical composition described herein, compared to the activity ofa different protein. In certain embodiments, the activity of BTK isselectively inhibited by a compound or pharmaceutical compositiondescribed herein, compared to the activity of a different protein.

The selectivity of a compound or pharmaceutical composition describedherein in inhibiting the activity of a protein kinase over a differentprotein (e.g., a different protein kinase) may be measured by thequotient of the IC₅₀ value of the compound or pharmaceutical compositionin inhibiting the activity of the different protein over the IC₅₀ valueof the compound or pharmaceutical composition in inhibiting the activityof the protein kinase. The selectivity of a compound or pharmaceuticalcomposition described herein for a protein kinase over a differentprotein may also be measured by the quotient of the K_(d) value of anadduct of the compound or pharmaceutical composition and the differentprotein over the K_(d) value of an adduct of the compound orpharmaceutical composition and the protein kinase. In certainembodiments, the selectivity is at least 2-fold, at least 3-fold, atleast 5-fold, at least 10-fold, at least 30-fold, at least 100-fold, atleast 300-fold, at least 1,000-fold, at least 3,000-fold, at least10,000-fold, at least 30,000-fold, or at least 100,000-fold. In certainembodiments, the selectivity is not more than 100,000-fold, not morethan 10,000-fold, not more than 1,000-fold, not more than 100-fold, notmore than 10-fold, or not more than 2-fold. Combinations of theabove-referenced ranges (e.g., at least 2-fold and not more than10,000-fold) are also within the scope of the disclosure.

In some embodiments, the activity of a protein kinase is non-selectivelyinhibited by the compounds or pharmaceutical compositions describedherein.

In certain embodiments, the activity of a protein kinase describedherein is aberrant. In certain embodiments, the activity of a proteinkinase described herein is increased. In certain embodiments, theactivity of a protein kinase described herein is increased compared tonormal (i.e., non-cancerous) cells.

In some proliferative diseases, such as MYD88 L265P driven Waldenström'smacroglobulinemia, certain protein kinase (e.g., a Src family kinase(e.g., HCK), BTK) is activated. Thus the compounds and pharmaceuticalcompositions may be useful in treating and/or preventing proliferativediseases by, e.g., inhibiting the activity of protein kinases.

Another aspect of the present disclosure relates to methods of treatinga proliferative disease in a subject in need thereof, the methodscomprising administering to the subject an effective amount (e.g.,therapeutically effective amount) of a compound or pharmaceuticalcomposition described herein.

Another aspect of the present disclosure relates to methods ofpreventing proliferative disease in a subject in need thereof, themethods comprising administering to the subject an effective amount(e.g., prophylactically effective amount) of a compound orpharmaceutical composition described herein.

In certain embodiments, the compounds and pharmaceutical compositionsare useful in treating and/or preventing proliferative diseases, such asproliferative diseases associated with MYD88. MYD88 gene has beenimplicated in many proliferative diseases. Activated B cell type diffuselarge B cell lymphoma (ABC-DLBCL), a particularly aggressive subtype ofDLBCL whose pathogenesis relies on constitutively active NFκB, isfrequently associated with MYD88 mutations. 39% of tumor samples containmutations in MYD88, and 29% of those mutations result in a singlenucleotide change from leucine into proline at position 265 (L265P) (Ngoet al., Nature. 2011 Feb. 3; 470(7332):115-9). shRNA knockdown of MYD88in lymphoma cell lines demonstrated that MYD88 mutations are criticalfor their survival and high NFκB transcription factor activity (Ngo etal., Nature. 2011 Feb. 3; 470(7332):115-9). A hyperphosphorylatedisoform of IRAK1 was strongly associated with the L265P mutant form ofMYD88, suggesting that this mutation is a gain-of-function mutation thatleads to the constitutive activation of downstream IRAKs (Ngo et al.,Nature. 2011 Feb. 3; 470(7332):115-9). The effects of the L265P mutationinclude increased NFκB activity as well as increased JAK-STAT3 signalingand the production of pro-inflammatory cytokines such as IL-6, IL-10,and IFN-β (Ngo et al., Nature. 2011 Feb. 3; 470(7332):115-9). Theproduction of these cytokines further activates JAK-STAT3 signaling aspart of an autocrine loop that enhances the survival of the lymphomacells (Lam et al., Blood. 2008 Apr. 1; 111(7):3701-13; Ding et al.,Blood. 2008 Feb. 1; 111(3):1515-23).

MYD88 mutations have since been seen in a number of other humanmalignancies, with the L265P mutation found in almost 100% ofWaldenström's macroglobulinemia (WM), 2-10% of chronic lymphocyticleukemia (CLL), 69% of cutaneous diffuse large B cell lymphoma (CBCL),and 38% of primary central nervous system lymphoma (PCNSL) (Wang et al.,Blood Lymphat Cancer (2013) 2013:53-6110). However, the effect of singleMYD88 L265P mutation on tumor growth is confounded by the accumulationof other potential damaging mutations in the same malignant clones.Recently, a retroviral gene transfer strategy to study the effects ofsingle MYD88 mutation in otherwise normal mature B cells found that theMYD88 L265P mutation alone was able to drive limited rounds of mitogenindependent B cell proliferation both in vitro and in vivo (Wang et al.,J Exp Med. 2014 Mar. 10; 211(3):413-26). Nevertheless, the drive for Bcell proliferation was dependent on intact nucleic acid sensingtoll-like receptor (TLR) activity since Unc93b13d mutation or Tlr9deficiency inhibited the proliferation of MYD88 L265P B cells in vitro(Wang et al., J Exp Med (2014) 211:413-2610). Other studies have alsoshown that oncogenic MYD88 depends on TLRs by using the depletion ofUNC91B1, PRAT4A, and CD14 in ABC-DLBCL lines as well as by usingpharmacological inhibitors to TLR7 and TLR9 (Lim et al. In: Proceedingsof the 104th Annual Meeting of the American Association for CancerResearch; 2013 Apr. 6-10; Washington, D.C. Philadelphia: AACR; CancerRes; (2013) 73(8 Suppl):Abst 2332.10.1158/1538-7445. AM2013-2332). Giventhat intact TLR activity is critical for lymphoma cells carrying MYD88mutations, targeting this pathway appears to be attractive for treatingthese malignancies. Indeed, blocking endosome acidification usingchloroquine selectively inhibits MYD88 L265P mutation driven B cellproliferation in vitro (Wang et al., J Exp Med (2014) 211:413-2610).

In certain embodiments, a subject described herein is diagnosed ashaving WM. The subject may present one or more signs, symptoms, orclinical features of WM including anemia, hyper-viscosity, neuropathy,coagulopathies, splenomegaly, hepatomegaly, adenopathy, and an IgM serumparaprotein. In certain embodiments, the subject is diagnosed as havingWM on the basis that the subject has a mutation at position 38182641 ofchromosome 3p22.2. In some embodiments, the mutation results in a singlenucleotide change from T to C in the MYD88 gene. In some embodiments,the mutation results in an amino acid change from leucine to proline atposition 265 in the MYD88 gene. The mutation may be detected in abiological sample obtained from the subject using any suitable methodknown in the art, including but not limited to, direct sequencing ofnucleic acid molecules, HPLC analysis, DNA chip technologies, and massspectroscopy.

In certain embodiments, a proliferative disease that is treated and/orprevented by a method described herein is a proliferative diseaseassociated with an MYD88 mutation (e.g., MYD88 L265P mutation). Incertain embodiments, the proliferative disease is cancer. In certainembodiments, the proliferative disease is a hematological malignancy. Incertain embodiments, the proliferative disease is myelodysplasia. Incertain embodiments, the proliferative disease is leukemia. In certainembodiments, the proliferative disease is chronic lymphocytic leukemia(CLL). In certain embodiments, the proliferative disease is lymphoma. Incertain embodiments, the proliferative disease is Waldenström'smacroglobulinemia. In certain embodiments, the proliferative disease isactivated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL), centralnervous system (CNS) lymphoma (e.g., primary CNS lymphoma, secondary CNSlymphoma), lymphoma of an immune privileged site, testicular lymphoma,or marginal zone lymphoma. In certain embodiments, the proliferativedisease is cerebral lymphoma, ocular lymphoma, lymphoma of the placenta,or lymphoma of the fetus. In certain embodiments, the proliferativedisease is a benign neoplasm. In certain embodiments, the proliferativedisease is pathological angiogenesis. In certain embodiments, theproliferative disease is an inflammatory disease. In certainembodiments, the proliferative disease is an autoimmune disease.

In certain embodiments, a method described herein further includesadministering to the subject an additional pharmaceutical agent. Incertain embodiments, a method described herein further includescontacting the biological sample with an additional pharmaceuticalagent. In certain embodiments, a method described herein furtherincludes contacting the tissue with an additional pharmaceutical agent.In certain embodiments, a method described herein further includescontacting the cell with an additional pharmaceutical agent. In certainembodiments, a method described herein further includes radiotherapy,immunotherapy, and/or transplantation (e.g., bone marrowtransplantation).

Another aspect of the present disclosure relates to methods of inducingapoptosis in a cell, the methods comprising contacting the cell with aneffective amount of a compound or pharmaceutical composition describedherein. Without wishing to be bound by any particular theory, thecompounds and pharmaceutical compositions described herein may be ableto inhibit the proliferation of and/or to kill cells, such as malignantcells (e.g., malignant cells whose proliferation and/or survival aredriven by MYD88 L265P expression). In certain embodiments, a compound orpharmaceutical composition described herein inhibits the proliferationof a cell by at least 10%, at least 20%, at least 30%, at least 40%, atleast 50%, at least 70%, or at least 90%. In certain embodiments, acompound or pharmaceutical composition described herein inhibits theproliferation of a cell by not more than 10%, not more than 20%, notmore than 30%, not more than 40%, not more than 50%, not more than 70%,or not more than 90%. In certain embodiments, a compound orpharmaceutical composition described herein kills at least 10%, at least20%, at least 30%, at least 40%, at least 50%, at least 70%, or at least90% cells. In certain embodiments, a compound or pharmaceuticalcomposition described herein kills not more than 10%, not more than 20%,not more than 30%, not more than 40%, not more than 50%, not more than70%, or not more than 90% cells. Combinations of the above-referencedranges (e.g., at least 10% and not more than 50%) are also within thescope of the disclosure.

Methods of Screening a Library of Compounds

Another aspect of the disclosure relates to methods of screening alibrary of compounds, and pharmaceutical acceptable salts thereof, toidentify a compound, or a pharmaceutical acceptable salt thereof, thatis useful in the methods of the disclosure. In certain embodiments, themethods of screening a library include obtaining at least two differentcompounds described herein; and performing at least one assay using thedifferent compounds described herein. In certain embodiments, at leastone assay is useful in identifying a compound that is useful in thedescribed methods.

Typically, the methods of screening a library of compounds involve atleast one assay. In certain embodiments, the assay is performed todetect one or more characteristics associated with the treatment of aproliferative disease (e.g., myelodysplasia, leukemia, lymphoma (e.g.,Waldenström's macroglobulinemia)) in a subject in need thereof, with theprevention of a proliferative disease (e.g., myelodysplasia, leukemia,lymphoma (e.g., Waldenström's macroglobulinemia)) in a subject in needthereof, with the inhibition of the activity of a protein kinase (e.g.,HCK, BTK) in a subject, biological sample, tissue, or cell, and/or withthe induction of apoptosis in a cell. The characteristics may be desiredcharacteristics (e.g., a proliferative disease in a subject having beentreated, a subject having been prevented from having a proliferativedisease, the activity of a protein kinase (e.g., HCK, BTK) in a subject,biological sample, tissue, or cell having been inhibited, and/or theapoptosis in a cell having been induced). The characteristics may beundesired characteristics (e.g., a proliferative disease in a subjecthaving not been treated, a subject having not been prevented from havingnot a proliferative disease, the activity of a protein kinase (e.g.,HCK, BTK) in a subject, biological sample, tissue, or cell having notbeen inhibited, and/or the apoptosis in a cell having not been induced).The assay may be an immunoassay, such as a sandwich-type assay,competitive binding assay, one-step direct test, two-step test, or blotassay. The step of performing at least one assay may be performedrobotically or manually. In certain embodiments, the assay comprises (a)contacting a library of compounds with a protein kinase; and (b)detecting the binding of the library of compounds to the protein kinase.In certain embodiments, the assay comprises detecting the specificbinding of the library of compounds to the protein kinase. In certainembodiments, the detected binding of the library of compounds to theprotein kinase is useful in identifying the compound that is useful inthe methods of the disclosure. In certain embodiments, the step ofdetecting the binding comprises using differential scanning fluorimetry(DSF), isothermal titration calorimetry (ITC), and/or an amplifiedluminescence proximity homogeneous assay (ALPHA). The step of performingat least one assay may be performed in a cell in vitro, ex vivo, or invivo. In certain embodiments, the step of performing at least one assayis performed in a cell in vitro. In certain embodiments, the assaycomprises (a) contacting a library of compounds with a cell; and (b)detecting a decrease in cell proliferation, an increase in cell death,and/or an increase in cell differentiation.

Uses

In another aspect, the present disclosure provides the compoundsdescribed herein for use in a method of the disclosure.

In still another aspect, the present disclosure provides thepharmaceutical compositions described herein for use in a method of thedisclosure.

In still another aspect, the present disclosure provides uses of thecompounds described herein in a method of the disclosure.

In further another aspect, the present disclosure provides uses of thepharmaceutical compositions described herein in a method of thedisclosure.

EXAMPLES

In order that the present disclosure may be more fully understood, thefollowing examples are set forth. The synthetic and biological examplesdescribed in this application are offered to illustrate the compounds,pharmaceutical compositions, and methods provided herein and are not tobe construed in any way as limiting their scope.

Preparation of the Compounds

The compounds provided herein can be prepared from readily availablestarting materials using the following general methods and procedures(e.g., Examples 1 to 21). Where typical or preferred process conditions(i.e., reaction temperatures, times, mole ratios of reactants, solvents,pressures, etc.) are given, other process conditions can also be usedunless otherwise stated. Optimum reaction conditions may vary with theparticular reactants or solvents used, but such conditions can bedetermined by those skilled in the art by routine optimizationprocedures.

General Methods and Materials for Preparing Exemplary CompoundsDescribed Herein

The following general methods and materials may be independentlyapplicable to any one of Examples 1 to 21. Commercially availablereagents and solvents were used without further purification. Allreactions were monitored by thin layer chromatography (TLC) with 0.25 mmE. Merck pre-coated silica gel plates (60 F254) and/or Waters LCMSsystem (Waters 2489 UV/Visible Detector, Waters 3100 Mass, Waters 515HPLC pump, Waters 2545 Binary Gradient Module, Waters Reagent Manager,Waters 2767 Sample Manager) using SunFire™ C18 column (4.6×50 mm, 5 mparticle size): Method A; solvent gradient=97% A at 0 min, 0% A at 5min; solvent A=0.035% TFA in Water; solvent B=0.035% TFA in MeOH; flowrate: 2.5 mL/min. Purification of reaction products was carried out byflash chromatography using CombiFlash® Rf with Teledyne Isco RediSep® RfHigh Performance Gold or Silicycle SiliaSep™ High Performance columns (4g, 12 g, or 24 g) and Waters LCMS system using SunFire™ Prep C₁₋₈ column(19×50 mm, 5 m particle size): solvent gradient=100% A at 0 min, 20% Aat 6 min; solvent A=0.035% TFA in Water; solvent B=0.035% TFA in MeOH;flow rate: 25 mL/min. The purity of all compounds was over 95% and wasanalyzed with Waters LCMS system. ¹H NMR spectra were obtained using aVarian Inova-500 or 600 (500 or 600 MHz for ¹H NMR) spectrometer.Chemical shifts are reported relative to chloroform (6=7.26) or dimethylsulfoxide (6=2.50) for ¹H NMR. Data are reported as (br=broad,s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet).

General Procedure I for the Aromatic Nucleophilic Displacement Reaction

The following General procedure I may be independently applicable to anyone of Examples 1 to 21. A microwave vial was charged with2-((2-chloropyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamide(1 eq), the amine analogue (2 eq) and anhydrous sec-butanol (0.05 M).The vial was sealed and was heated in the Biotage Initiator microwave at160° C. until the reaction had reached completion. The solvent wasremoved under reduced pressure and the residue redissolved in DCM, andTFA was added and the reaction mixture was stirred at ambienttemperature for 2 h. The solvent was removed under reduced pressure andthe residue was purified by preparative HPLC.

General Procedure II for the Acrylamide Formation

The following General procedure II may be independently applicable toany one of Examples 1 to 21. The amine intermediate (1 eq) was dissolvedin a 1:1 mixture of THF and saturated NaHCO₃ aqueous solution, andcooled to 0° C. To the stirring mixture was added a dilute solution ofacryloyl chloride (3 eq) in THF, the reaction was stirred at 0° C. andgradually warmed to ambient temperature. After 30 min, the reaction wasextracted with ethyl acetate twice, the organic extracts were combinedand concentrated under reduced pressure. The residue was directlypurified by preparative HPLC.

Example 1. Preparation of(S)-2-((2-((1-acryloylpyrrolidin-3-yl)amino)pyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamide

Methyl 2-((2-chloropyrimidin-4-yl)amino)thiazole-5-carboxylate

A solution of a mixture of 2-chloropyrimidin-4-amine (5.0 g, 38.5 mmol)and methyl 2-chlorothiazole-5-carboxylate (6.85 g, 38.5 mmol, 1equivalent (eq)) in dry N,N-dimethylformamide (75 ml) was cooled to 0°C. and was treated portionwise over 5 min with sodium hydride (60% w/win mineral oil, 3.1 g, 76.9 mmol, 2 eq). The reaction mixture wasstirred at 0° C. for 1 h and warmed to ambient temperature for a further1 h. The mixture was treated with saturated ammonium chloride, followedby saturated aqueous Na₂CO₃ solution to reach pH 9, and the resultingmixture was extracted with 1:1 mixture of dichloromethane and ethylacetate. The organic extracts were combined, dried using a hydrophobicfrit, and evaporated under reduced pressure. The residue was purified bychromatography on silica to afford the title compound as an off-whitesolid. LCMS retention time (RT): 2.70 (Method A), Mass m/z: 270.99(M+1).

2-((2-Chloropyrimidin-4-yl)amino)thiazole-5-carboxylic acid

To a solution of methyl2-((2-chloropyrimidin-4-yl)amino)thiazole-5-carboxylate (1 g, 3.7 mmol)in 1:1 mixture of THF/H₂O (15 mL) was added LiOH monohydrate (2.6 g,29.6 mmol, 8 eq), and the reaction mixture was stirred at ambienttemperature for 12 h. After 12 h, the reaction mixture was concentratedunder reduced pressure and cooled to 0° C., and concentrated HCl wasadded dropwise to reach pH 6. The precipitate was filtered, washed withcold water, and dried using a hydrophobic frit to afford the titledcompound as a white solid. LCMS RT: 2.13 (Method A), Mass m/z: 257.05(M+1).

2-((2-Chloropyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamide

To a solution of 2-((2-chloropyrimidin-4-yl)amino)thiazole-5-carboxylicacid (50 mg, 0.195 mmol) in toluene (1 mL) was added thionyl chloride(2.26 mL, 1.95 mmol, 10 eq). The reaction mixture was stirred at 90° C.for 3 h, cooled to room temperature (rt), and concentrated under reducedpressure. The crude was dissolved in 1,2-dichloroethane (DCE, 1 mL), and2,6-dimethylaniline (48 μL, 0.390 mmol, 2 eq) and DIPEA(N,N-diisopropylethylamine, 68 μL, 0.390 mmol, 2 eq) was added. Thereaction mixture was stirred at 80° C. for 12 h and cooled to ambienttemperature, and water was added. The mixture was extracted withisopropanol/chloroform (1:4) three times, the organic extracts werecombined, washed with brine, dried over Na₂SO₄, and concentrated underreduced pressure. The residue was purified by chromatography on silicato afford the title compound as a yellowish solid. LCMS RT: 2.95 (MethodA), Mass m/z: 360.22 (M+1).

N-(2-Chloro-6-methylphenyl)-2-((2-chloropyrimidin-4-yl)amino)thiazole-5-carboxamide

N-(2-chloro-6-methylphenyl)-2-((2-chloropyrimidin-4-yl)amino)thiazole-5-carboxamidewas prepared from 2-((2-chloropyrimidin-4-yl)amino)thiazole-5-carboxylicacid and 2-chloro-6-methylaniline using the same procedure. LCMS RT:2.98 (Method A), Mass m/z: 380.26 (M+1).

(S)-2-((2-((1-acryloylpyrrolidin-3-yl)amino)pyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamide

(S)-2-((2-((1-acryloylpyrrolidin-3-yl)amino)pyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamidewas prepared from2-((2-chloropyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamideand tert-butyl (S)-3-aminopyrrolidine-1-carboxylate using generalprocedures I and II. LCMS RT: 2.23 (Method A), Mass m/z: 464.48 (M+1).

Example 2. Preparation of(S)—N-(2,6-dimethylphenyl)-2-((2-((1-propionylpyrrolidin-3-yl)amino)pyrimidin-4-yl)amino)thiazole-5-carboxamide

(S)—N-(2,6-dimethylphenyl)-2-((2-((1-propionylpyrrolidin-3-yl)amino)pyrimidin-4-yl)amino)thiazole-5-carboxamidewas prepared from2-((2-chloropyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamide,tert-butyl (S)-3-aminopyrrolidine-1-carboxylate and propionyl chlorideusing general procedures I and II. LCMS RT: 2.28 (Method A), Mass m/z:466.62 (M+1). 1H NMR (400 MHz,) δ 12.47 (s, 1H), 9.77 (s, 1H), 8.53 (s,1H), 8.38-8.28 (m, 1H), 8.08 (dd, J=6.4, 3.1 Hz, 1H), 7.13 (d, J=1.8 Hz,3H), 6.44 (t, J=5.5 Hz, 1H), 4.51 (d, J=98.4 Hz, 1H), 3.97-2.94 (m, 3H),2.28-2.21 (m, 1H), 2.19 (d, J=2.0 Hz, 6H), 2.08 (t, J=7.5 Hz, 1H), 1.97(d, J=8.8 Hz, 1H), 1.01-0.91 (m, 3H), 0.91-0.78 (m, 2H).

Example 3. Preparation of(R)-2-((2-((1-acryloylpyrrolidin-3-yl)amino)pyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamide

(R)-2-((2-((1-acryloylpyrrolidin-3-yl)amino)pyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamidewas prepared from2-((2-chloropyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamideand tert-butyl (R)-3-aminopyrrolidine-1-carboxylate using generalprocedures I and II. LCMS RT: 2.23 (Method A), Mass m/z: 464.54 (M+1).1H NMR (400 MHz,) δ 12.47 (s, 1H), 9.77 (s, 1H), 8.46 (s, 1H), 8.33 (d,J=5.3 Hz, 1H), 8.08 (d, J=6.6 Hz, 1H), 7.12 (s, 3H), 6.66-6.40 (m, 2H),6.12 (ddd, J=17.3, 5.8, 2.5 Hz, 1H), 5.71-5.59 (m, 1H), 4.57 (d, J=69.4Hz, 1H), 4.04-2.75 (m, 3H), 2.19 (s, 6H), 2.35-1.93 (m, 1H), 1.33-0.66(m, 2H).

Example 4. Preparation of(R)-2-((2-((1-acryloylpiperidin-3-yl)amino)pyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamide

(R)-2-((2-((1-acryloylpiperidin-3-yl)amino)pyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamidewas prepared from2-((2-chloropyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamideand tert-butyl (R)-3-aminopiperidine-1-carboxylate using generalprocedures I and II. LCMS RT: 2.10 (Method A), Mass m/z: 478.53 (M+1).

Example 5. Preparation of2-((2-((1-acryloylazepan-3-yl)amino)pyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamide

2-((2-((1-acryloylazepan-3-yl)amino)pyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamidewas prepared from2-((2-chloropyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamideand tert-butyl 3-aminoazepane-1-carboxylate using general procedures Iand II. LCMS RT: 2.50 (Method A), Mass m/z: 492.59 (M+1). 1H NMR (400MHz, DMSO-d6) δ 9.80 (s, 1H), 8.34 (s, 1H), 8.23 (s, 1H), 8.09 (d, J=6.5Hz, 1H), 7.13 (s, 3H), 6.78 (dd, J=16.6, 10.5 Hz, 1H), 6.45 (d, J=6.7Hz, 1H), 6.06 (d, J=16.6 Hz, 1H), 5.64 (d, J=10.6 Hz, 1H), 4.48 (s, 1H),3.42 (s, 5H), 2.19 (s, 6H), 1.80-1.50 (m, 4H), 1.23 (m, 1H), 0.84 (m,1H).

Example 6. Preparation of2-((2-(((1-acryloylpyrrolidin-3-yl)methyl)amino)pyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamide

2-((2-(((1-acryloylpyrrolidin-3-yl)methyl)amino)pyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamidewas prepared from2-((2-chloropyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamideand tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate using generalprocedures I and II. LCMS RT: 2.25 (Method A), Mass m/z: 478.60 (M+1).1H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 9.83 (d, J=8.8 Hz, 1H), 8.48(s, 1H), 8.35 (s, 1H), 8.06 (d, J=6.5 Hz, 1H), 7.14 (s, 3H), 6.52 (dd,J=16.8, 9.2 Hz, 1H), 6.42 (t, J=5.6 Hz, 1H), 6.11-5.99 (m, 1H),5.60-5.40 (m, 1H), 4.00-2.97 (m, 4H), 2.82-2.54 (m, 1H), 2.20 (s, 6H,overlap), 2.17-1.97 (m, 1H), 1.87-1.55 (m, 1H), 1.24 (m, 1H), 0.85 (d,J=7.2 Hz, 1H).

Example 7. Preparation of(S)-2-((2-((1-acryloylpyrrolidin-3-yl)amino)pyrimidin-4-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

(S)-2-((2-((1-acryloylpyrrolidin-3-yl)amino)pyrimidin-4-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamidewas prepared fromN-(2-chloro-6-methylphenyl)-2-((2-chloropyrimidin-4-yl)amino)thiazole-5-carboxamideand tert-butyl (S)-3-aminopyrrolidine-1-carboxylate using generalprocedures I and II. LCMS RT: 2.25 (Method A), Mass m/z: 484.52 (M+1).1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.43 (d, J=6.7 Hz, 1H), 8.30(s, 1H), 8.06 (s, 1H), 7.44-7.31 (m, 1H), 7.31-7.17 (m, 2H), 6.34 (d,J=6.2 Hz, 1H), 6.23-6.02 (m, 2H), 5.58 (d, J=9.9 Hz, 1H), 3.43 (s, 4H),2.21 (s, 4H), 1.95 (s, 1H), 1.36-1.02 (m, 1H), 0.82 (s, 1H).

Example 8. Preparation of2-((2-((1-acryloylazepan-3-yl)amino)pyrimidin-4-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

2-((2-((1-acryloylazepan-3-yl)amino)pyrimidin-4-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamidewas prepared fromN-(2-chloro-6-methylphenyl)-2-((2-chloropyrimidin-4-yl)amino)thiazole-5-carboxamideand tert-butyl 3-aminoazepane-1-carboxylate using general procedures Iand II. LCMS RT: 2.50 (Method A), Mass m/z: 512.69 (M+1).

Example 9. Preparation of(S)-2-((2-((1-acryloylpyrrolidin-3-yl)amino)-6-(morpholinomethyl)pyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamide

Methyl2-((2-chloro-6-(morpholinomethyl)pyrimidin-4-yl)amino)thiazole-5-carboxylate

A solution of a mixture of 2-chloropyrimidin-4-amine (730 mg, 3.2 mmol)and methyl 2-chlorothiazole-5-carboxylate (626 mg, 3.5 mmol, 1.1 eq) indry N,N-dimethylformamide (15 ml) was cooled to 0° C. and was treatedportionwise over 5 min with sodium hydride (60% w/w in mineral oil, 256mg, 6.4 mmol, 2 eq). The reaction mixture was stirred at 0° C. for 1 hand warmed to ambient temperature for a further 1 h. The mixture wastreated with saturated ammonium chloride, followed by saturated aqueousNa₂CO₃ solution to reach pH 9 and the product was extracted with 1:1mixture of dichloromethane and ethyl acetate. The organic extracts werecombined, dried using a hydrophobic frit and evaporated under reducedpressure. The residue was purified by chromatography on silica to affordthe title compound as an off-white solid. LCMS RT: 2.07 (Method A), Massm/z: 370.37 (M+1).

2-((2-chloro-6-(morpholinomethyl)pyrimidin-4-yl)amino)thiazole-5-carboxylicacid

To a solution of methyl2-((2-chloro-6-(morpholinomethyl)pyrimidin-4-yl)amino)thiazole-5-carboxylate(190 mg, 0.51 mmol) in THF/H₂O (1:2 mixture, 6 mL), was added LiOHmonohydrate (32 mg, 0.77 mmol, 1.5 eq) in one portion and the reactionmixture was stirred at ambient temperature for 12 h. After 12 h, thereaction mixture was concentrated under reduced pressure and cooled to0° C. and concentrated HCl was added dropwise to reach pH 6. Theprecipitate was filtered, washed with cold water, dried using ahydrophobic frit to afford the titled compound as a white solid. LCMSRT: 1.67 (Method A), Mass m/z: 356.24 (M+1).

2-((2-chloro-6-(morpholinomethyl)pyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamide

To a solution of2-((2-chloro-6-(morpholinomethyl)pyrimidin-4-yl)amino)thiazole-5-carboxylicacid (175 mg, 0.49 mmol) in toluene (3 mL) was added thionyl chloride(5.68 mL, 4.9 mmol, 10 eq). The reaction mixture was stirred at 90° C.for 3 h before cooled to room temperature and concentrated under reducedpressure. The crude was dissolved in DCE and 2,6-dimethylaniline andDIPEA was added. The reaction mixture was stirred at 80° C. for 12 hbefore cooled to ambient temperature and water was added. The mixturewas extracted with isopropanol/chloroform (1:4) three times, the organicextracts were combined, washed with brine and dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified bychromatography on silica to afford the title compound as a yellowishsolid. LCMS RT: 2.23 (Method A), Mass m/z: 479.48 (M+1).

2-((2-chloro-6-(morpholinomethyl)pyrimidin-4-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

2-((2-chloro-6-(morpholinomethyl)pyrimidin-4-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamidewas prepared from2-((2-chloro-6-(morpholinomethyl)pyrimidin-4-yl)amino)thiazole-5-carboxylicacid and 2-chloro-6-methylaniline using the same procedure.

(S)-2-((2-((1-acryloylpyrrolidin-3-yl)amino)-6-(morpholinomethyl)pyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamide

(S)-2-((2-((1-acryloylpyrrolidin-3-yl)amino)-6-(morpholinomethyl)pyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamidewas prepared from2-((2-chloro-6-(morpholinomethyl)pyrimidin-4-yl)amino)-N-(2,6-dimethylphenyl)thiazole-5-carboxamideand tert-butyl (S)-3-aminopyrrolidine-1-carboxylate following generalprocedures I and II. LCMS RT: 2.10 (Method A), Mass m/z: 563.55 (M+1).

Example 10. Preparation of(S)-2-((2-((1-acryloylpyrrolidin-3-yl)amino)-6-(morpholinomethyl)pyrimidin-4-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

(S)-2-((2-((1-acryloylpyrrolidin-3-yl)amino)-6-(morpholinomethyl)pyrimidin-4-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamidewas prepared from2-((2-chloro-6-(morpholinomethyl)pyrimidin-4-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamideand tert-butyl (S)-3-aminopyrrolidine-1-carboxylate following generalprocedures I and II. LCMS RT: 2.17 (Method A), Mass m/z: 583.52 (M+1).

Example 11. Preparation of2-((1-((1-acryloylpyrrolidin-3-yl)methyl)-1H-pyrazol-3-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

tert-butyl 3-((3-nitro-1H-pyrazol-1-yl)methyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl3-((((trifluoromethyl)sulfonyl)oxy)methyl)pyrrolidine-1-carboxylate(1.47 g, 4.98 mmol) and 3-nitro-1H-pyrazole (619 mg, 5.48 mmol, 1.1 eq)in DMF (25 mL) was added K₂CO₃ (2.06 g, 14.94 mmol, 3 eq) in oneportion, the reaction mixture was stirred at 60° C. for 12 h. Themixture was cooled to ambient temperature and extracted with ethylacetate, the combined extracts were washed with water, 1N HCl and brine,dried over Na₂SO₄ and concentrated under reduced pressure to yield thetitle compound, as a crude and used directly in the next step. LCMS RT:3.78 (Method A), Mass m/z: 300.06 (M+1).

tert-butyl 3-((3-amino-1H-pyrazol-1-yl)methyl)pyrrolidine-1-carboxylate

tert-butyl 3-((3-nitro-1H-pyrazol-1-yl)methyl)pyrrolidine-1-carboxylatewas dissolved in ethanol, 10 wt % Pd/C was added to the solution and thereaction mixture was stirred under H₂ atmosphere at ambient temperaturefor 3 h. The suspension was filtered through a pad of celite and thefiltrate concentrated under reduced pressure to afford the titlecompound. LCMS RT: 1.97 (Method A), Mass m/z: 267.33 (M+1).

tert-butyl 3-((3-amino-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

tert-butyl 3-((3-amino-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylatewas prepared using tert-butyl3-((((trifluoromethyl)sulfonyl)oxy)methyl)piperidine-1-carboxylate and3-nitro-1H-pyrazole following the same procedure. LCMS RT: 2.18 (MethodA), Mass m/z: 281.21 (M+1).

tert-butyl3-((3-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-1H-pyrazol-1-yl)methyl)pyrrolidine-1-carboxylate

To a solution of2-bromo-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (75 mg, 0.23mmol) and tert-butyl3-((3-amino-1H-pyrazol-1-yl)methyl)pyrrolidine-1-carboxylate (120 mg,0.45 mmol, 2 eq) in sec-butanol (1 mL) was added K₂CO₃ (94 mg, 0.68mmol, 3 eq). The reaction mixture was degassed via sonication, beforePd₂(dba)₃ (12.4 mg, 0.014 mmol, 0.06 eq) and xantphos (12.0 mg, 0.020mmol, 0.09 eq) were added to the mixture. The reaction was stirred at80° C. for 3 h, filtered and dried under reduced pressure, and theresidue was purified by preparative HPLC to yield the title compound.LCMS RT: 3.57 (Method A), Mass m/z: 517.61 (M+1).

tert-butyl3-((3-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

tert-butyl3-((3-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylatewas prepared from tert-butyl3-((3-amino-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate and2-bromo-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide following thesame procedure. LCMS RT: 3.65 (Method A), Mass m/z: 531.66 (M+1).

tert-butyl4-(4-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate

tert-butyl4-(4-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylatewas prepared from tert-butyl4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate and2-bromo-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide following thesame procedure. LCMS RT: 3.28 (Method A), Mass m/z: 517.61 (M+1).

2-((1-((1-acryloylpyrrolidin-3-yl)methyl)-1H-pyrazol-3-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

tert-butyl3-((3-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-1H-pyrazol-1-yl)methyl)pyrrolidine-1-carboxylatewas dissolved in a 1:1 mixture of DCM and TFA. The reaction was stirredat ambient temperature for 2 h and dried under reduced pressure. Theresidue was dissolved in a 1:1 mixture of THF and saturated NaHCO₃aqueous solution and cooled to 0° C. To the stirring mixture was added adilute solution of acryloyl chloride in THF, the reaction was stirred at0° C. and gradually warmed to ambient temperature. After 30 min, thereaction was extracted with Ethyl acetate twice, the organic extractscombined and concentrated under reduced pressure. The residue wasdirectly purified by preparative HPLC to yield the title compound. LCMSRT: 2.98 (Method A), Mass m/z: 485.47 (M+1). 1H NMR (400 MHz, DMSO-d6) δ11.12 (s, 1H), 9.78 (d, J=8.4 Hz, 1H), 8.13 (d, J=6.4 Hz, 1H), 7.69 (t,J=2.6 Hz, 1H), 7.43-7.19 (m, 3H), 6.54 (dd, J=16.8, 10.3 Hz, 1H), 6.07(ddd, J=16.9, 5.1, 2.4 Hz, 1H), 5.95 (dd, J=9.7, 2.2 Hz, 1H), 5.61 (ddd,J=10.2, 7.8, 2.5 Hz, 1H), 4.11 (d, J=7.3 Hz, 1H), 3.57-3.40 (m, 3H),3.25 (m, 1H), 2.80-2.60 (m, 1H), 2.23 (s, 3H), 1.97 (ddt, J=41.2, 12.5,6.3 Hz, 1H), 1.67 (ddd, J=45.6, 12.8, 7.7 Hz, 1H).

Example 12. Preparation of2-((1-((1-acryloylpiperidin-3-yl)methyl)-1H-pyrazol-3-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

2-((1-((1-acryloylpiperidin-3-yl)methyl)-1H-pyrazol-3-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamidewas prepared from tert-butyl3-((3-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylatefollowing the same procedure. LCMS RT: 2.83 (Method A), Mass m/z: 471.60(M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.79 (s, 1H), 8.13 (s,1H), 7.67 (d, J=2.3 Hz, 1H), 7.38 (dd, J=7.5, 2.0 Hz, 1H), 7.32-7.16 (m,2H), 6.70 (ddd, J=51.7, 16.7, 10.4 Hz, 1H), 6.02 (dd, J=16.7, 2.4 Hz,1H), 5.96 (d, J=2.3 Hz, 1H), 5.59 (t, J=12.6 Hz, 1H), 4.22-3.91 (m, 4H),3.14-2.80 (m, 2H), 2.23 (s, 3H), 1.98 (s, 1H), 1.68 (d, J=12.1 Hz, 2H),1.44-1.16 (m, 2H).

Example 13. Preparation of2-((1-(1-acryloylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

2-((1-(1-acryloylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamidewas prepared from tert-butyl4-(4-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylatefollowing the same procedure. LCMS RT: 2.67 (Method A), Mass m/z: 471.41(M+1).

Example 14. Preparation ofN-(1-methyl-1H-pyrazol-3-yl)-5-phenoxythiazolo[5,4-b]pyridin-2-amine

2-bromo-6-phenoxypyridin-3-amine

To a solution of 6-phenoxypyridin-3-amine (2 g, 10.8 mmol) in DMF (20mL) was added N-bromosuccinimide (1.91 g, 10.8 mmol, 1 eq) at −10° C.for 5 min. The reaction mixture was quenched with saturated. NaHCO₃solution at −10° C. The mixture was partitioned between ethyl acetateand water. The organic layer was separated and the aqueous layer wasextracted with ethyl acetate. The combined organic extracts were washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure.The crude product was purified by flash column chromatography to affordtitle compound as a reddish brown solid. LCMS RT: 3.33 (Method A), Massm/z: 261.21 (M+1).

2-(methylthio)-5-phenoxythiazolo[5,4-b]pyridine

To a solution of 2-bromo-6-phenoxypyridin-3-amine (2.29 g, 8.64 mmol) inNMP (80 mL) was added potassium ethyl xanthogenate (6.9 g, 43.2 mmol, 5eq) and acetic acid (3.1 mL, 43.2 mmol, 5 eq). The reaction mixture washeated at 150° C. for 16 hours. The mixture was cooled to 50° C. andiodomethane (538 μL, 86.4 mmol, 10 eq) was added. The reaction mixturewas further stirred for 30 minutes and partitioned between ethyl acetateand water. The organic layer was separated and the aqueous layer wasextracted with ethyl acetate. The combined organic extracts were washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure.The residue was purified by flash column chromatography to afford titlecompound as a bright brown solid. LCMS RT: 3.95 (Method A), Mass m/z:275.21 (M+1).

2-(methylsulfonyl)-5-phenoxythiazolo[5,4-b]pyridine

To a solution of 2-(methylthio)-5-phenoxythiazolo[5,4-b]pyridine (3.0 g,11 mmol) in THF (18 mL) and methanol (18 mL) was added Oxone (6.66 g, 44mmol, 4 eq) in water (18 mL). The reaction mixture was stirred for 16hours at room temperature. The reaction mixture was filtered andconcentrated under reduced pressure to give the title product as abright brown solid. LCMS RT: 3.38 (Method A), Mass m/z: 307.19 (M+1).N-(1-methyl-1H-pyrazol-3-yl)-5-phenoxythiazolo[5,4-b]pyridin-2-amine

To a solution of 2-(methylsulfonyl)-5-phenoxythiazolo[5,4-b]pyridine and1-methyl-1H-pyrazol-3-amine (30 mg, 0.1 mmol) in sec-butanol (1 mL) wasadded HCl in dioxane (0.1 mL). The reaction mixture was heated in theBiotage Initiator microwave at 160° C. until the reaction had reachedcompletion. The solvent was removed under reduced pressure and theresidue purified directly by preparative HPLC. LCMS RT: 3.23 (Method A),Mass m/z: 324.09 (M+1).

Example 15. Preparation ofN-(1-methyl-1H-pyrazol-4-yl)-5-phenoxythiazolo[5,4-b]pyridin-2-amine

N-(1-methyl-1H-pyrazol-4-yl)-5-phenoxythiazolo[5,4-b]pyridin-2-amine wasprepared from 2-(methylsulfonyl)-5-phenoxythiazolo[5,4-b]pyridine and1-methyl-1H-pyrazol-4-amine following the same procedure. LCMS RT: 3.18(Method A), Mass m/z: 324.15 (M+1).

Example 16. Preparation of5-phenoxy-N-(1-(tetrahydro-2H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-amine

5-phenoxy-N-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-aminewas prepared from 2-(methylsulfonyl)-5-phenoxythiazolo[5,4-b]pyridineand 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine following the sameprocedure. LCMS RT: 3.22 (Method A), Mass m/z: 394.45 (M+1).

Example 17. Preparation of(S)-1-(3-((4-((5-phenoxythiazolo[5,4-b]pyridin-2-yl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one

N-(2-chloropyrimidin-4-yl)-5-phenoxythiazolo[5,4-b]pyridin-2-amine

A solution of 2-(methylsulfonyl)-5-phenoxythiazolo[5,4-b]pyridine and2-chloropyrimidin-4-amine (192 mg, 1.49 mmol) in DMF (9 mL) was cooledto 0° C. and NaH (184 mg, 4.47 mmol, 3 eq, 60% in mineral) was added tothe stirring mixture. The reaction was warmed to ambient temperature andstirred for a further 2 h. The mixture was treated with saturatedammonium chloride. Saturated aqueous Na₂CO₃ was added to reach pH 9 andthe product was extracted with 1:1 mixture of dichloromethane and ethylacetate. The organic extracts were combined, dried using a hydrophobicfrit and evaporated to dryness. The residue was purified bychromatography on silica to afford the title compound as an off-whitesolid. LCMS RT: 3.62 (Method A), Mass m/z: 356.24 (M+1).

(S)-1-(3-((4-((5-phenoxythiazolo[5,4-b]pyridin-2-yl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one

(S)-1-(3-((4-((5-phenoxythiazolo[5,4-b]pyridin-2-yl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl)prop-2-en-1-onewas prepared fromN-(2-chloropyrimidin-4-yl)-5-phenoxythiazolo[5,4-b]pyridin-2-amine andtert-butyl (S)-3-aminopyrrolidine-1-carboxylate following generalprocedures I and II. LCMS RT: 2.62 (Method A), Mass m/z: 460.51 (M+1).

Example 18. Preparation of(R)-1-(3-((4-((5-phenoxythiazolo[5,4-b]pyridin-2-yl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one

(R)-1-(3-((4-((5-phenoxythiazolo[5,4-b]pyridin-2-yl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl)prop-2-en-1-onewas prepared fromN-(2-chloropyrimidin-4-yl)-5-phenoxythiazolo[5,4-b]pyridin-2-amine andtert-butyl (R)-3-aminopyrrolidine-1-carboxylate following generalprocedures I and II. LCMS RT: 2.47 (Method A), Mass m/z: 460.51 (M+1).

Example 19. Preparation of(S)-1-(3-((4-((5-phenoxythiazolo[5,4-b]pyridin-2-yl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one

(S)-1-(3-((4-((5-phenoxythiazolo[5,4-b]pyridin-2-yl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)prop-2-en-1-onewas prepared fromN-(2-chloropyrimidin-4-yl)-5-phenoxythiazolo[5,4-b]pyridin-2-amine andtert-butyl (S)-3-aminopiperidine-1-carboxylate following generalprocedures I and II. LCMS RT: 2.57 (Method A), Mass m/z: 474.56 (M+1).

Example 20. Preparation of(R)-1-(3-((4-((5-phenoxythiazolo[5,4-b]pyridin-2-yl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one

(R)-1-(3-((4-((5-phenoxythiazolo[5,4-b]pyridin-2-yl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)prop-2-en-1-onewas prepared fromN-(2-chloropyrimidin-4-yl)-5-phenoxythiazolo[5,4-b]pyridin-2-amine andtert-butyl (R)-3-aminopiperidine-1-carboxylate following generalprocedures I and II. LCMS RT: 2.55 (Method A), Mass m/z: 474.50 (M+1).

Example 21. Preparation of1-(3-((4-((5-phenoxythiazolo[5,4-b]pyridin-2-yl)amino)pyrimidin-2-yl)amino)azepan-1-yl)prop-2-en-1-one

1-(3-((4-((5-phenoxythiazolo[5,4-b]pyridin-2-yl)amino)pyrimidin-2-yl)amino)azepan-1-yl)prop-2-en-1-onewas prepared fromN-(2-chloropyrimidin-4-yl)-5-phenoxythiazolo[5,4-b]pyridin-2-amine andtert-butyl 3-aminoazepane-1-carboxylate following general procedures Iand II. LCMS RT: 2.73 (Method A), Mass m/z: 488.49 (M+1).

Example 22. Inhibitory Activities of Exemplary Compounds DescribedHerein Against Select Protein Kinases and Cells

The inhibitory activities of exemplary compounds described hereinagainst select protein kinases and cells were determined. Cell survivalfollowing treatment of exemplary compounds described herein was assessedby CellTiter-Glo® Luminescent cell viability assay (Promega). The cellswere seeded into 384 well plates with the EL406 Combination WasherDispenser (BioTek Instruments, Inc.), and a series diluted exemplarycompounds (20˜0.0006 μM) were injected into the culture media with theJANUS Automated Workstation (PerkinElmer Inc.). The cells were treatedfor 72 hours at 37° C. with 5% CO₂. Luminescent measurement is performedusing the 2104 Envision® Multilabel Reader (PerkinElmer Inc.). EC₅₀values were calculated with GRAPHPAD PRISM software. Exemplary resultsare shown in Table 1B.

TABLE 1B Exemplary biological data of exemplary compounds describedherein. BTK HCK BCWM.1 MWCL-1 TMD-8 HBL-1 IC₅₀ IC₅₀ EC₅₀ EC₅₀ EC₅₀ EC₅₀Compound (nM) (nM) (nM) (nM) (nM) (nM) Dasatinib 1.20 7.41 18.70 190.00I-1 1.61 0.59 73.40 50.00 301.00 522.00 I-3 0.60 <0.495 19.30 55.20158.00 669.00 I-6 1.90 4.24 69.60 93.70 80.20 229.00 I-2 1.63 0.73 41.0067.00 311.00 1670.00 I-4 1.38 0.59 53.00 85.00 315.00 449.00 I-7 <0.495<0.495 22.00 19.00 49.00 70.00 I-8 <0.495 <0.495 75.00 103.00 301.00522.00 I-10 1.74 2.42 170.00 191.00 1010.00 1640.00 I-11 5.52 3.99129.00 245.00 500.00 623.00 III-1 86.60 1820.00 1830.00 4080.00 3850.003200.00 III-2 281.00 402.00 916.00 1350.00 2640.00 2960.00 III-3 19.402150.00 2710.00 5750.00 4130.00 2960.00 III-4 367 1150 808 2160 21202550 III-5 9.06 1910 1190 3370 1230 896 III-6 2580 4550 270 2170 467 450III-7 >10000 >10000 >20000 >20000 >20000 >20000 III-8 >10000 >100007250 >20000 14600 >20000 III-9 2660 7200 8290 16600 18300 >20000 II-11.1 1.64 84 121 573 735 II-2 <0.495 1.94 196 166 929 1000 II-3 19.9 25.3690 772 2540 3650 I-9 0.5 <0.495 9.84 25 70.9 220 I-12 75.50 317.00453.00 1200.00 OCI-Ly3 OCI-Ly19 Ramos OCI-Ly7 RPMI-8226 OPM-2 EC₅₀ EC₅₀EC₅₀ EC₅₀ EC₅₀ EC₅₀ Compound (nM) (nM) (nM) (nM) (nM) (nM) Dasatinib8060.00 3860.00 4560.00 155.00 5390.00 7110.00 I-1 NA NA NA I-3 39500.0013000.00 >20000 370.00 I-6 NA NA NA 520.00 I-2 >20000 >20000 >20000 I-44270 >20000 I-7 399 133 I-8 3770 7970 I-5 I-10 5700 12 I-11 3680 1580III-1 1250 3700 III-2 1100 2300 III-3 2500 8460 III-4 1170 2190 III-51330 2720 III-6 321 749 III-7 9520 >20000 III-8 12600 >20000 III-9 706011800 II-1 7880 >20000 II-2 6540 >20000 II-3 9970 >20000 I-9 1450010000 >20000 I-12 309.00 NA: Not available.

Example 23. KINATIV Assay of Compounds I-3 and I-9

BCWM.1 cells were treated with compound I-3 or I-9 (1 μM) for 90minutes. The cells were harvested and lysed. The lysates were dividedinto two parts: one part was directly labeled with an ATP-biotin probe(no GENEFILTERS (GF)), and the other part was first gel-filtered, and,15 minutes after gel-filtering, probe labeled (GENEFILTERS (GF)). Boundkinases were identified and quantitated by ACTIVX as described inPatricelli et al., Biochemistry, 2007, 46(2): 350-358. The compoundswere tested in duplicates against duplicate or quadruplicate controlsamples. Exemplary results are shown in Table 2, where the % changes ofMS (mass spectroscopy) signals of compounds I-3 or I-9, compared to thecontrol samples, are reported. The results shown in Table 2 werestatistically significant (Student T-test score <0.04). A compoundinhibited the kinase activity when a % change of the MS signal shown inTable 2 is positive (e.g., greater than 0%) or increased the kinaseactivity when a % change of the MS signal shown in Table 2 is negative(e.g., lower than 0%).

TABLE 2 Exemplary KINATIV assay results of compounds 1-3 and 1-9.% change of MS signal compared to control sample I-3 I-9 I-3 I-9Labeling 1 μM 1 μM 1 μM 1 μM Kinase Reference Sequence Site no GF GFno GF GF ABL, ARG UniRef100_P00519 LMTGDTYTAHAGA Activation 75.4 46.193.5 75.4 KFPIK Loop ABL, ARG UniRef100_P00519, YSLTVAVKTLKED Lys1 86.940.6 93.2 71.8 UniRef100_P42684 TMEVEEFLK ACK UniRef100_Q07912TVSVAVKCLKPDV Lys1 5.8 15.6 52.7 2.4 LSQPEAMDDFIR AGK UniRef100_Q53H12ATVFLNPAACKGK ATP −0.2 −12.4 ATK1 UniRef100_P31749 GTFGKVILVK ATP Loop−20.4 −25.1 −21.9 −16.8 AKT2, AKT3 UniRef100_Q9Y243, GTFGKVILVR ATP Loop−19.2 −9.7 −14.5 5.4 UniRef100_P31751 AMPKa1, UniRef100_P54646,DLKPENVLLDAHM Lys2 −7.6 22.1 12.1 5.8 AMPKa2 UniRef100_Q96E92 NAK ARAFUniRef100_P10398 DLKSNNIFLHEGL Lys2 −152.4 −56.6 −402.1 −95.1 TVK ATMUniRef100_Q13315 QLVKGRDDLRQDA ATP 20.7 19.5 VMQQVFQMCNTLL QR ATRUniRef100_Q13535 FYIMMCKPK ATP −31.6 28.1 25.3 16.5 AurAUniRef100_O14965 FILALKVLFK Lys1 12 −14.5 −13 1.4 AurA UniRef100_O14965DIKPENLLLGSAG Lys2 12.7 −6.6 −5.9 1.2 ELK AurA, AurB, UniRef100_O14965,GKFGNVYLAR ATP Loop 7.7 5.5 4.7 2.8 AurC UniRef100_Q9UQB9,UniRef100_Q96GD4 AurB UniRef100_Q96GD4 SHFIVALKVLFK Lys1 −2.2 −20.6−23.6 −21.5 BLK UniRef100_P51451 IIDSEYTAQEGAK Activation >96 93.7 >9695.4 FPIK Loop BRAF UniRef100_P15056 DLKSNNIFLHEDL Lys2 −7.6 −18.3 −48.9−12.9 TVK BTK UniRef100_Q06187 YVLDDEYTSSVGS Activation 94.7 96.7 95.270.7 KFPVR Loop CaMK1d UniRef100_Q8IU85 LFAVKCPIK Lys1 −0.4 −7.5 −5 −4.6CaMK2d UniRef100_Q13557 IPTGQEYAAKIIN Lys1 −1.3 −8.1 −25 −8.2 TKK CaMK2gUniRef100_Q13555 TSTQEYAAKIINT Lys1 13.7 −17.7 −12 −4.4 K CaMK4UniRef100_Q16566 DLKPENLLYATPA Lys2 6.8 −10.3 −0.1 −13.1 PDAPLK CaMKK2UniRef100_Q96RR4 DIKPSNLLVGEDG Lys2 −2.1 −4.9 1.7 0.5 HIK CASKUniRef100_O14936 ETGQQFAVKIVDV Lys1 −1 −10.4 0.5 3.9 AK CDC2UniRef100_Q5H9N4 DLKPQNLLIDDKG Protein −0.7 −2.6 −4.3 −3.2 TIK KinaseDomain CDC7 UniRef100_O00311 DVKPSNFLYNR Lys2 −12.5 −2.2 CDK11,UniRef100_P49336, DLKPANILVMGEG Lys2 −15.2 28.6 20.4 11.8 CDK8UniRef100_Q9BWU1 PER CDK2 UniRef100_P24941 DLKPQNLLINTEG Lys2 3.6 −8.71.2 −4.3 AIK CDK4 UniRef100_P11802 DLKPENILVTSGG Lys2 10.3 1.2 4.8 3.4TVK CDK5 UniRef100_Q00535 DLKPQNLLINR Lys2 11.8 −1.1 −1.8 7.7 CDK6UniRef100_Q00534 DLKPQNILVTSSG Lys2 12.4 2.7 3.6 3.5 QIK CDK7UniRef100_P50613 DLKPNNLLLDENG Lys2 8.9 1.3 5.1 5.1 VLK CDK9UniRef100_P50750 DMKAANVLITR Lys2 −1.7 32.7 25.9 23.1 CHEDUniRef100_Q14004 DIKSCNILLNNR Lys2 5.7 15.3 CHK1 UniRef100_B4DT73DIKPENLLLDER Lys2 9.7 −25.9 5.6 −2 CHK2 UniRef100_O96017 DLKPENVLLSSQELys2 8.2 −13.1 −11.9 −2.5 EDCLIK CK1a UniRef100_P48729 DIKPDNFLMGIGRLys2 −18.2 32.6 30.6 12.5 CK1d, CK1e UniRef100_P49674, DVKPDNFLMGLGKLys2 −16.5 26.3 10.8 12.8 UniRef100_P48730 K CK1g1, UniRef100_Q9Y6M4,KIGCGNFGELR ATP Loop −8.2 −4.7 CK1g2, UniRef100_P78368, CK1g3UniRef100_Q9HCP0 CK1g2 UniRef100_P78368 DVKPENFLVGRPG Lys2 −3.7 −8.9−4.5 −10.9 TK CK2a2 UniRef100_P19784 DVKPHNVMIDHQQ Lys2 −8.7 7 4 −1.8 KCLK1 UniRef100_P49759 LTHTDLKPENILF Lys2 −25 −6.2 VQSDYTEAYNPK CLK2UniRef100_P49760 LTHTDLKPENILF Lys2 −19.3 −10.6 VNSDYELTYNLEK CLK3UniRef100_P49761 YEIVGNLGEGTFG ATP Loop 17.6 −19 3.6 −10.3 KVVECLDHARCOT UniRef100_P41279 GAFGKVYLAQDIK ATP Loop −37.3 −40.3 CRK7UniRef100_Q9NYV4 DIKCSNILLNNSG Lys2 13 27.8 QIK CSK UniRef100_P41240VSDFGLTKEASST Activation 36 −6 60.3 1.5 QDTGKLPVK Loop DGKAUniRef100_P23743 IDPVPNTHPLLVF ATP −5.2 −1.5 −24 −6.6 VNPKSGGK DGKHUniRef100_Q86XP1 ATFSFVCVSPLLV ATP 15.2 −21.2 −44.1 −12.5 FVNSKSGDNQGVKDLK UniRef100_Q12852 DLKSPNMLITYDD Lys2 10.2 −8 VVK DNAPKUniRef100_P78527 KGGSWIQEINVAE ATP −2.2 −0.3 10.5 −0.4 K DNAPKUniRef100_P78527 EHPFLVKGGEDLR ATP −15.1 −35.1 11 3.4 eEF2KUniRef100_O00418 YIKYNSNSGFVR ATP −18.9 −51.4 −27.8 −48.7 EGFRUniRef100_P00533 IPVAIKELR Lys1 20 17 EphB1 UniRef100_P54762YLQDDTSDPTYTS Activation 92.9 53.3 95.7 78.9 SLGGKIPVR Loop EphB2UniRef100_P29323 FLEDDTSDPTYTS Activation 91 81.7 91.6 85.6 ALGGKIPIRLoop Erk1 UniRef100_P27361 DLKPSNLLINTTC Lys2 −0.6 −3.1 1.5 3.1 DLK Erk2UniRef100_P28482 DLKPSNLLLNTTC Lys2 −1.8 −3.8 1.1 4 DLK Erk3UniRef100_Q16659 DLKPANLFINTED Lys2 23.2 16.9 23.8 25.3 LVLK Erk5UniRef100_Q13164 DLKSPNLLVNENC Lys2 3 −1.8 8.3 1.1 ELK FERUniRef100_P16591 TSVAVKTCKEDLP Lys1 9.1 −8.4 −14 2.6 QELK FESUniRef100_P08332 LRADNTLVAVKSC Lys1 10.7 −11.2 −13.3 −3.9 R FGRUniRef100_P09769 LIKDDEYNPCQGS Activation 95.7 84.7 95.4 72.1 KFPIK LoopFRAP UniRef100_P42345 IQSIAPSLQVITS ATP 6.9 −8.1 −21.4 2.2 KQRPR FRKUniRef100_P42685 HEIKLPVK Activation 92.4 36.7 95.8 73.6 Loop FYNUniRef100_P06241 VAIKTLKPGTMSP Lys1 >91 >91 ESFLEEAQIMK FYN, SRC,UniRef100_P12931, QGAKFPIKWTAPE Activation 87.3 72.5 85.7 80.4 YESUniRef100_P07947, AALYGR Loop UniRef100_P06241 GAK UniRef100_O14976DLKVENLLLSNQG Lys2 −14.5 33.8 TIK GCK UniRef100_Q12851 DIKGANLLLTLQGLys2 18.1 4.5 17.8 16.4 DVK GCN2 UniRef100_Q9P2K8 DLKPVNIFLDSDD Lys2−2.8 −18.8 −14.3 −10.7 HVK GSK3A UniRef100_P49840 DIKPQNLLVDPDT Lys2 3.52.3 9 1.9 AVLK GSK3B UniRef100_P49841 DIKPQNLLLDPDT Lys2 9.4 −9.8 −0.5−1.3 AVLK HPK1 UniRef100_Q92918 DIKGANILINDAG Lys 18.8 −2.9 5.9 7.3 EVRIKKa UniRef100_O15111 DLKPENIVLQDVG Lys2 14.6 −3.3 −4.4 −0.4 GK IKKbUniRef100_O14920 DLKPENIVLQQGE Lys2 3.6 0.4 −6.4 −1.4 QR IKKeUniRef100_Q14164 SGELVAVKVFNTT Lys1 5.5 −12.6 −21.5 −6.1 SYLRPR ILKUniRef100_Q13418 WQGNDIVVKVLK Lys1 3.2 −1.9 −9.7 1.2 ILKUniRef100_Q13418 ISMADVKFSFQCP Protein 3.6 24.5 9.7 12.4 GR KinaseDomain IRAK1 UniRef100_P51617 AIQFLHQDSPSLI Lys2 −4.8 −2.6 −19.8 −3.2HGDIKSSNVLLDE R IRAK3 UniRef100_Q9Y616 VEIQNLTYAVKLF Lys1 −11.3 7.2 −5.5−1.4 K IRAK4 UniRef100_Q9NWZ3 DIKSANILLDEAF Lys2 16.4 −3.2 −11 6.2 TAKIRE1 UniRef100_O75460 DLKPHNILISMPN Lys2 −12.1 24.3 13.2 2 AHGK ITPK1UniRef100_Q13572 ESIFFNSHNVSKP ATP 8.5 −10 1.5 1.7 ESSSVLTELDKIEGVFERPSDEVIR JAK1 UniRef100_P23458 QLASALSYLEDKD Protein 12.3 −11.5 −25−6.7 LVHGNVCTKNLLL Kinase AR Domain JAK1 UniRef100_P23458 IGDFGLTKAIETDActivation −2.9 −15.6 −1.6 −13.9 domain2 KEYYTVK Loop JAK1UniRef100_P23458 YDPEGDNTGEQVA Lys1 −2.1 −18.1 −29.1 −14.4 domain2VKSLKPESGGNHI ADLKK JAK3 UniRef100_P52333 IADFGLAKLLPLD Activation −1.5−21.6 −0.6 13.5 domain2 KDYYVVR Loop JNK1, JNK2, UniRef100_P45983,DLKPSNIVVK Lys2 14.9 −7 4.7 0.5 JNK3 UniRef100_P53779, UniRef100_P45984KHS1 UniRef100_Q9Y4K4 NVHTGELAAVKII Lys1 −7.5 −8.7 K KHS2UniRef100_Q8IVH8 NVNTGELAAIKVI Lys1 −23.6 −22.7 K KSR1 UniRef100_Q8IVT5SKNVFYDNGKVVI Activation 7.1 −8.7 −41.8 −25.6 TDFGLFGISGVVR LoopKSR1, KSR2 UniRef100_Q6VAB6, SKNVFYDNGK Activation −4.3 −14.6 −24.2−16.2 UniRef100_Q8IVT5 Loop LATS1 UniRef100_O95835 ALYATKTLR Lys1 14.6−2.8 −5.2 5.4 LATS2 UniRef100_Q9NRM7 DIKPDNILIDLDG Lys2 9.4 −12.3 −17.9−5.1 HIK LCK UniRef100_P06239 EGAKFPIKWTAPE Activation 92.6 61.6 92.782.8 AINYGTFTIK Loop LKB1 UniRef100_Q15831 DIKPGNLLLTTGG Lys2 −11.2−11.2 −8.7 −7.4 TLK LOK UniRef100_O94804 DLKAGNVLMTLEG Lys2 −8.6 26.28.5 15.2 DIR LRRK2 UniRef100_Q5S007 DLKPHNVLLFTLY Lys2 11.6 −26.4 −6.6−21.7 PNAAIIAK LYN UniRef100_P07948 VAVKTLKPGTMSV Lys1 >98 85.2 >98 94QAFLEEANLMK MAP2K1 UniRef100_Q02750 IMHRDVKPSNILV Lys2 0.1 28.5 25 3.5NSR MAP2K1, UniRef100_P36507, KLIHLEIKPAIR Lys1 13.5 −9.2 −5.7 −1.1MAP2K2 UniRef100_Q02750 MAP2K1, UniRef100_P36507, DVKPSNILVNSR Lys2 20.8−6.4 −6.9 −4.5 MAP2K2 UniRef100_Q02750 MAP2K2 UniRef100_P36507HQIMHRDVKPSNI Lys2 −3.5 34.6 16.5 12.5 LVNSR MAP2K3 UniRef100_P46734DVKPSNVLINK Lys2 15.6 −21.3 5.8 −3.6 MAP2K4 UniRef100_P35985 DIKPSNILLDRLys2 −3.9 −5.4 1.1 −2.1 MAP2K5 UniRef100_Q13163 DVKPSNMLVNTR Lys2 −2.216.8 44.4 16.3 MAP2K6 UniRef100_P52564 DVKPSNVLINALG Lys2 10.6 −22.1 −2−5.9 QVK MAP2K7 UniRef100_O14733 DVKPSNILLDER Lys2 1.5 −2.8 −9.1 −0.3MAP3K1 UniRef100_Q13233 DVKGANLLIDSTG Lys2 22.5 11.1 18.8 9.8 QR MAP3K2UniRef100_Q9Y2U5 ELAVKQVQFDPDS Lys1 −2.1 −16.2 −21.7 −8.3 PETSKEVNALECEIQLLK MAP3K2, UniRef100_Q9Y2U5, DIKGANILR Lys2 15.3 0.7 −12.6 6.8 MAP3K3UniRef100_Q99759 MAP3K3 UniRef100_Q99759 ELASKQVQFDPDS Lys1 13.2 −13.7−40.9 −19.7 PETSKEVSALECE IQLLK MAP3K4 UniRef100_Q9Y6R4 DIKGANIFLTSSGLys2 16.8 3.2 1.2 10.9 LIK MAP3K5 UniRef100_Q99683 DIKGDNVLINTYS Lys28.3 −9 −5.9 8.1 GVLK MAP3K6 UniRef100_O95382 DIKGDNVLINTFS Lys2 15.9−13.4 −15.4 −5 GLLK MARK2, UniRef100_P27448, DLKAENLLLDADM Lys2 −17.627.8 16.2 9.5 MARK3 UniRef100_Q7KZIY NIK MARK3 UniRef100_P27448EVAIKIIDKTQLN Lys1 7.9 −6.4 −12.9 −4.8 PTSLQK MARK3, UniRef100_Q97L34,EVAIKIIDK Lys1 2.5 −10.4 −4 −7.1 MARK4 UniRef100_P27448 UniRef100_Q96L34DLKAENLLLDAEA Lys2 −8.5 −12.2 −8.7 −10.2 NIK MAST1, UniRef100_Q6P0Q8,DLKPDNLLITSMG Lys2 −13.4 22 26.3 −0.5 MAST2 UniRef100_Q9Y2H9 HIK MAST3UniRef100_O60307 DLKPDNLLITSLG Lys2 8.1 −22.1 −11.9 −11.9 HIK MASTLUniRef100_Q96GX5 GAFGKVYLGQK ATP Loop 5.3 0.4 6 1.8 MASTLUniRef100_Q96GX LYAVKVVK Lys1 16.4 2.4 9.8 8 MELK UniRef100_Q14680DLKPENLLFDEYH Lys2 −12.1 −9.6 −10.6 −9.5 K MER UniRef100_Q12866NCMLRDDMTVCVA Activation 6.3 −12.5 DFGLSKK Loop MER, UniRef100_Q06418,KIYSGDYYR Activation 2.4 −14.7 0.4 3.1 TYRO3 UniRef100_Q12866 Loop METUniRef100_P08581 DMYDKEYYSVHNK Activation −12.9 −45.2 Loop MLK1UniRef100_P80192 DLKSSNILILQK Lys2 1 9 MLK3 UniRef100_Q16584DLKSNNILLLQPI Lys2 −7.2 24.1 6.3 3.9 ESDDMEHK MLK4 UniRef100_Q5TCX8DLKSSNILLLEK Lys2 −3.8 −22 −11.8 −18.5 MLKL UniRef100_Q8NB16 APVAIKVFKLys1 −5.6 −4.7 −4.6 −3.9 MPSK1 UniRef100_O75716 DLKPTNILLGDEG Lys2 −9.721.9 20.9 10.1 QPVLMDLGSMNQA CIHVEGSR MSK1 UniRef100_O75582DIKLENILLDSNG Lys2 −2.8 −22.8 −9 −23.9 domain HVVLTDFGLSK MSK2UniRef100_O75676 DLKLENVLLDSEG Lys2 −2 −27 −17.3 −18.7 domainHIVLTDFGLSK MST1 UniRef100_Q13043 ETGQIVAIKQVPV Lys1 −4.5 −28.8 −20.9−11.3 ESDLQEIIK MST2 UniRef100_Q13188 ESGQVVAIKQVPV Lys1 −12.1 −24.9 −18−11.9 ESDLQEIIK MST3 UniRef100_Q9Y6E0 DIKAANVLLSEHG Lys2 −2 −1.9 −3.8−1.4 EVK MST4 UniRef100_Q9P289 TQQVVAIKIIDLE Lys1 −6.7 −31.5 −36.1 −20EAEDEIEDIQQEI TVLSQCDSSYVTK MST4, UniRef100_O00506, DIKAANVLLSEQG Lys218.1 9.7 15.5 15.2 YSK1 UniRef100_Q9P289 DVK NDR1 UniRef100_Q15208DIKPDNLLLDSK Lys2 2.3 −4.2 −5.5 2.8 NDR2 UniRef100_Q9Y2H1 DIKPDNLLLDAKLys2 11.6 −5.6 −9.6 2.9 NEK1 UniRef100_Q96PY6 DIKSQNIFLTK Lys2 7.4 −3.7−7.6 4.6 NEK2 UniRef100_P51955 DLKPANVFLDGK Lys2 20.5 −8.2 0.9 4.3 NEK3UniRef100_P59156 SKNIFLTQNGK Activation −21.2 −3.2 Loop NEK4UniRef100_P51957 DLKTQNVFLTR Lys2 10.1 −13.1 7.3 −1.7 NEK6, NEK7UniRef100_Q8TDX7, DIKPANVFITATG Lys2 6.4 −3.3 −13.1 −0.8UniRef100_Q9HC98 VVK NEK7 UniRef100_Q8TDX7 AACLLDGVPVALK Lys1 5.7 11.3−14.7 8 K NEK8 UniRef100_Q86SG6 DLKTQNILLDK Lys2 5.1 −14.1 −14.5 −5.8NEK9 UniRef100_Q8TD19 DIKTLNIFLTK Lys2 15.4 −21.3 −9.9 −12.6 NLKUniRef100_Q9UBE8 DIKPGNLLVNSNC Lys2 66.2 −1.2 85.9 51.8 VLK OSR1UniRef100_C9JIG9, DVKAGNILLGEDG Lys2 13.8 2.7 4 13.9 UniRef100_O95747SVQIADFGVSAFL ATGGDITR p38a UniRef100_Q16539 DLKPSNLAVNEDC Lys2 43.5−7.8 70 9.8 ELK Protein 32.6 −2.9 67.9 8.7 p38a UniRef100_Q16539QELNKTIWEVPER Kinase Domain p38d, UniRef100_Q015264, DLKPGNLAVNEDC Lys25.7 −8.8 −0.7 −27.1 p38g UniRef100_P53778 ELK p70S6K UniRef100_P23443DLKPENIMLNHQG Lys2 −77.2 15.9 −51.5 −8.6 HVK p70S6Kb UniRef100_Q9UBS0DLKPENIMLSSQG Lys2 −36.7 24.3 6.8 3.1 HIK Protein −17.5 23.2 2.5 4 PAN3UniRef100_Q58A45 VMDPTKILITGK Kinase Domain PCTAIRE1 UniRef100_Q00536SKLTDNLVALEKI Lys1 10 4.1 −14.7 6.5 R PCTARIE2, UniRef100_Q00537,SKLTENLVALKEI Lys1 −0.4 −4.7 −12 −0.8 PCTAIRE3 UniRef100_Q07002 R PDK1UniRef100_O15530 EYAIKILEK Lys1 −8.4 −6.4 −3.5 −6.6 PEK UniRef100_Q9NZJ5DLKSPNIFFTMDD Lys2 −12.8 22.1 6.4 15.4 VVK PFTAIRE1 UniRef100_O94921LVALKVIR Lys1 0.9 −3.9 −6.6 −3.1 PHKg1 UniRef100_Q16816 DLKPENILLDDNMProtein 31.7 −51 −38.8 −26.2 NIK Kinase Domain PHKg2 UniRef100_P15735ATGHEFAVKIMEV Lys1 −31.2 12.5 22.3 5.3 TAER PI4K2B UniRef100_Q8TCG2SEEPYGQLNPWKT ATP 2.6 6.5 K PI4KA, UniRef100_A4QPH2, SGTMPQSAAKAPY ATP−3.7 20.3 12 3.6 PI4KAP2 UniRef100_P42356 LAK PIK4B UniRef100_Q9UBF8VPHTQAVVLNSKD ATP 6.4 −24.3 −4.1 −3.1 K PIK3C2B UniRef100_O00750VIFKCGDDLRQDM ATP −1.8 28.5 39.1 12.7 LTLQMIR PIK3C3 UniRef100_Q8NEB9TEDGGKYPVIFKH ATP 2.4 −23.4 −0.8 −9.4 GDDLR PIK3CB UniRef100_P42338VFGEDSVGVIFKN ATP −9.1 33.6 39.9 18.5 GDDLRQDMLTLQM LR PIK3CDUniRef100_O00329 VNWLAHNVSKDNR ATP −3.4 −19.7 −17.2 −9.7 Q PIK3CGUniRef100_P48736 KKPLWLEFK ATP −9.6 −15.1 −3.4 −9.6 PIP4K2AUniRef100_P48426 AKELPTLKDNDFI ATP −4.9 −10.5 −15.2 −8.3 NEGQK PIP4K2BUniRef100_P78356 AKDLPTFKDNDFL ATP 17.6 −19 NEGQK PIP4K2CUniRef100_Q8TBX8 TLVIKEVSSEDIA ATP −14.1 10 27 −3.9 DMHSNLSNYHQYI VKPIP5K1A UniRef100_Q99755 EKPLPTFKDLDFL ATP 26.2 30.5 QDIPDGLFLDADMYNALCK PIP5K3 UniRef100_Q9Y2I7 GGKSGAAFYATED ATP 6.5 −6.7 −4.6 −4.6DRFILK PITSLRE UniRef100_P21127 DLKTSNLLLSHAG Lys2 −14.1 −10.8 −8.6 −0.6ILK PKACa UniRef100_P17612 DLKPENLLIDQQG Lys2 −9.8 −8.4 YIQVTDFGFAKPKCa, UniRef100_P05771 DLKLDNVMLDSEG Lys2 2.4 16.9 3.3 25.3 PKCbUniRef100_P17252 HIK PKCe UniRef100_Q02156 DLKLDNILLDAEG Lys2 −38.2 −7HCK PKCi UniRef100_P41743 IYAMKVVK Lys1 16.5 18.6 PKCt UniRef100_Q04759GSFGKVFLAEFK ATP Loop −5.2 23.5 PKD2 UniRef100_Q9BZL6 DVAVKVIDK Lys1 5.5−11 −1.4 −4.2 PKD3 UniRef100_O94806 DVAIKVIDK Lys1 −15.2 −9.2 PKN1UniRef100_Q16512 VLLSEFRPSGELF Lys1 −3.3 −4.9 −29.4 −0.9 AIKALK PKN2UniRef100_Q16513 DLKLDNLLLDTEG Lys2 −4.5 13.6 FVK PKR UniRef100_P19525DLKPSNIFLVDTK Lys2 −3.6 −8 −17.6 −3.8 PLK1 UniRef100_P53350CFEISDADTKEVF Lys1 0.2 2.1 −23 9.6 AGKIVPK PRP4 UniRef100_113523CNILHADIKPDNI Lys2 5.9 −24.8 −6.2 −15.7 LVNESK PRPK UniRef100_Q96S44FLSGLELVKQGAE ATP Loop 2.1 −2 17.3 −1.2 AR PYK2 UniRef100_Q14289YIEDEDYYKASVT Activation 1 5.1 −12.1 −0.9 R Loop QSK UniRef100_Q9Y2K2DLKAENLLLDANL Lys2 −1.8 2.5 NIK RAF1 UniRef100_P04049 DMKSNNIFLHEGL Lys2−18.8 9.9 9.9 −9.2 TVK RIPK3 UniRef100_Q9Y572 DLKPSNVLLDPEL Lys2 13.4−15 22 −27 HVK ROCK1 UniRef100_Q13464 KLQLELNQER Protein 2.6 −7.3 −16.9−2.1 Kinase Domain ROCK1, UniRef100_O75116 DVKPDNMLLDK Lys2 −22.2 24.412.5 1.7 ROCK2 UniRef100_Q13464 RSK1 UniRef100_Q15418 DLKPENILLDEEG Lys29 −2 −16.9 −5.1 domain1 HIKLTDFGLSKEA IDHEK RSK1 UniRef100_P51812,DLKPENILLDEEG Lys2 −14.8 −12 −7.3 −6.1 domain1, UniRef100_115418, HIKRSK2 UniRef100_Q15349 domain1, RSK3 domain1 RSK1 UniRef100_Q15418DLKPSNILYVDES Lys2 −1.9 −9.7 −20.8 −4.1 domain2 GNPECLR RSK2UniRef100_P51812 DLKPENILLDEEG Lys2 −2 −5.6 −15.5 −8.4 domain1HIKLTDFGLSKES IDHEK RSK2 UniRef100_P51812 DLKPSNILYVDES Lys2 −10.2 −9.7−16.5 1.6 domain2 GNPESIR RSK3 UniRef100_Q15349 DLKPENILLDEEG Lys2 7.6−1.4 −19 −4.1 domain1 HIKITDFGLSK RSK4 UniRef100_Q9UK32 DLKPENILLDEIGLys2 9.1 15.8 domain1 HIK RSKL1 UniRef100_Q96S38 VLGVIDKVLLVMD ATP −1713.5 −25.8 1.8 TR SGK3 UniRef100_Q96BR1 FYAVKVLQK Lys1 −0.4 1.1 −18.5−1.1 SLK UniRef100_Q9H2G2 DLKAGNILFTLDG Lys2 13 −6 1.6 4.3 DIK SMG1UniRef100_Q96Q15 DTVTISHSVGGTI ATP 0.6 −11.6 −36.7 −1 TILPTKTKPK SNRKUniRef100_Q9NRH2 DLKPENVVFFEK Lys2 46.4 28.6 40.2 30.1 SRCUniRef100_P12931 VAIKTLKPGTMSP Lys1 91.7 78.6 96.7 81.1 EAFLQEAQVMKKSRPK1 UniRef100_Q96SB4 IIHTDIKPENILL Lys2 −7.8 −4 −16.8 −0.4 SVNEQYIRSRPK1, UniRef100_P78362, FVAMKVVK Lys1 −3 10 22.3 2.5 SRPK2UniRef100_Q96SB4 STK33 UniRef100_Q9BYT3 DLKLENIMVK Lys2 −6.1 20.2 11.816.1 STLK5 UniRef100_Q7RTN6 YSVKVLPWLSPEV Activation 10.4 −12.9 −17.7−9.4 LQQNLQGYDAK Loop STLK6 UniRef100_Q9C0K7 HTPTGTLVTIKIT Lys1 7.2 4.8NLENCNEER SYK UniRef100_P43405 ISDFGLSKALR Activation −1.2 −6.5 −1.1−6.1 Loop TAK1 UniRef100_O43318 DLKPPNLLLVAGG Lys2 2.3 −1.4 −2.5 1 TVLKTAO1, UniRef100_Q7L7X3, DIKAGNILLTEPG Lys2 7.8 5.1 14.3 9.3 TAO3UniRef100_Q9H2K8 QVK TAO2 UniRef100_Q9UL54 DVKAGNILLSEPG Lys2 5 4.3 811.5 LVK TBK1 UniRef100_Q9UHD2 TGDLFAIKVFNNI Lys1 −25.1 23 −1.6 10.8SFLRPVDVQMR TEC UniRef100_P42680 YVLDDQYTSSSGA Activation >91 97.4 >9140.8 KFPVK Loop TLK1 UniRef100_Q9UKI8 YLNEIKPPIIHYD Lys2 −0.7 −7.9 −6.9−2.3 LKPGNILLVDGTA CGEIK TLK2 UniRef100_Q86UE8 YLNEIKPPIIHYD Lys2 −3−13.3 4.7 −1.9 LKPGNILLVNGTA CGEIK TYK2 UniRef100_P29597 IGDFGLAKAVPEGActivation −10.1 −17.7 −5.5 −16.8 domain2 HEYYR Loop ULK1UniRef100_O85385 DLKPQNILLSNPA Lys2 9.9 −5.7 −8.2 −1.7 GR ULK3UniRef100_D3DW67 NISHLDLKPQNIL Lys2 8.2 −16.4 −47.2 −9.6 LSSLEKPHLK VRK2UniRef100_Q86Y07 MLDVLEYIHENEY Lys2 −13.9 6.2 5.7 −1.6 VHGDIKAANLLLG YKWee1 UniRef100_P30291 YIHSMSLVHMDIK Lys2 −32.7 14.3 −6.5 8.6 PSNIFISRWnk1, UniRef100_Q9Y3S1, GSFKTVYK ATP Loop 13.1 −6.3 6.8 7.6 Wnk2UniRef100_D3DUP1 Wnk1, UniRef100_Q9Y3S1, DLKCDNIFITGPT Lys2 14.9 −10.8−1.2 4.4 Wnk2, UniRef100_D3DUP1, GSVK Wnk3 UniRef100_Q9BYP7 YANK3UniRef100_Q86UX6 DVKPDNILLDER Lys2 −8.6 −13.2 YSK1 UniRef100_O00506EVVAIKIIDLEEA Lys1 −11.5 −20.8 EDEIEDIQQEITV LSQCDSPYITR ZAKUniRef100_Q9NYL2 WISQDKEVAVKK Lys1 1.6 −9.3 21.2 12.1 ZC1/HGKUniRef100_O95819 TGQLAAIKVMDVT Lys1 −14.8 20.9 −16.8 15.3 EDEEEEIKLEINMLKK ZC1/HGK, UniRef100_O95819, DIKGQVNLLTENA Lys2 2.7 −2 −0.1 1.8HZ2/TNIK, UniRef100_Q9UKE5, EVK ZC3,MINK UniRef100_Q9N4C8 ZC2/TNIKUniRef100_Q9UKE5 TGQLAAIKVMDVT Lys1 −15.6 23.4 32.9 11.4 GDEEEEIKQEINMLKK Labeling Site Key: Lys1: Conserved Lysine 1; Lys2: Conserved Lysine2; ATP Loop: ATP binding loop; Activation Loop: Activation loop; ATP:ATP site in non-canonical kinase (e.g. lipid kinase); Protein KinaseDomain: Other lysine within kinase domain, possibly not in ATP bindingsite; and Other: Labeling of residue outside of the protein kinasedomain, possibly not in ATP binding site.

Example 24. KINATIV Assay of Compounds I-4, I-7, I-8, and II-1

BCWM.1 cells were treated with compound I-4, I-7, I-8, or II-1 (1 μM)for 90 minutes. The cells were harvested and lysed. The lysates weredirectly labeled with an ATP-biotin probe. Bound kinases were identifiedand quantitated by ACTIVX as described in Patricelli et al.,Biochemistry, 2007, 46(2): 350-358. The compounds were tested induplicates against duplicate or quadruplicate control samples. Exemplaryresults are shown in Table 3, where the % changes of MS signals ofcompounds I-4, I-7, I-8, or II-1, compared to the control samples, arereported. The results shown in Table 3 were statistically significant(Student T-test score <0.04). A compound inhibited the kinase activitywhen a % change of the MS signal shown in Table 3 is positive (e.g.,greater than 0%) or increased the kinase activity when a % change of theMS signal shown in Table 3 is negative (e.g., lower than 0%).

TABLE 3 Exemplary KINATIV assay results of compounds I-4, I-7, I-8, andII-1. % change of MS signal compared to control sample I-4 I-7 I-8 II-1Kinase (1 μM) (1 μM) (1 μM) (1 μM) ABL, ARG 91.7 >97 >97 39.5 ABL,ARG >90 >90 >90 76.1 ACK 27.0 80.7 69.9 51.7 ACK 22.8 88.5 82.4 50.8AKT1 −11.0 −16.4 −19.5 −17.8 AMPKa1 10.1 2.7 −0.6 5.1 AMPKa1, AMPKa2−11.0 −20.7 −29.2 −19.4 AMPKa1, AMPKa2 −40.3 −22.3 −13.2 −27.3 ATR −66.1−48.0 −24.9 −55.3 AurA 3.7 −15.7 −15.2 −10.8 AurA 1.7 7.2 −0.1 3.6 AurA,AurB, AurC 2.3 0.4 −2.9 −3.6 AurB −10.1 −6.1 −14.3 −7.2 BARK1 −8.1 −29.7−19.6 −23.3 BLK >95 >95 >95 >95 BRAF 17.8 21.7 11.1 6.9 BTK 97.0 98.998.0 97.1 BTK >90 >90 >90 >90 CaMK1d −12.5 −19.1 −14.1 −7.9 CaMK1d −4.0−16.0 −8.7 −2.8 CaMK2a, CaMK2b, CaMK2d, CaM 10.0 7.4 10.4 2.5 K2g CaMK2d−8.5 −22.5 −22.3 −14.8 CaMK2g −19.8 −12.8 −9.4 −17.5 CaMK4 −7.1 −24.9−26.3 −10.3 CaMKK2 −1.5 28.6 17.3 16.1 CaMKK2 −10.2 −29.6 −27.8 −18.7CASK 23.2 37.7 43.0 29.4 CDC2 −24.9 −0.9 14.5 −5.2 CDC2 5.1 −16.2 −10.92.7 CDK11, CDK8 −36.1 −3.5 19.6 −9.2 CDK2 18.8 15.3 21.5 19.5 CDK2 3.5−2.1 −4.9 −1.1 CDK4 6.8 16.7 6.1 2.2 CDK5 −7.1 −27.5 −31.8 −11.2 CDK5−7.2 −14.0 −3.8 −8.0 CDK6 7.8 4.1 4.5 6.0 CDK7 21.6 0.7 −8.2 8.6 CDK716.8 22.2 20.6 22.6 CDK9 −41.9 −37.0 −5.2 −57.0 CHK1 −8.6 13.5 15.3 9.0CHK1 24.1 27.2 24.7 29.6 CHK2 −7.9 −18.6 −14.3 −8.3 CHK2 1.0 −5.6 −10.910.3 CK1a −41.3 −0.7 14.9 −14.4 CK1g2 −4.5 −3.7 −6.1 −1.1 CK2a1 24.614.3 13.9 24.7 CK2a2 −3.6 −6.4 27.5 13.8 CLK3 −1.3 −15.7 −14.9 −22.6 CSK35.7 76.5 88.1 26.2 CSK 35.7 75.7 86.2 32.5 DNAPK −80.8 −155.4 −153.0−117.2 DNAPK −12.9 −17.6 −26.7 −17.7 eEF2K 0.3 4.9 −1.5 −3.8EphB1 >97 >97 >97 91.0 EphB2 >90 >90 >90 >90 Erk1 −10.9 −23.1 −19.7−17.6 Erk2 −3.2 −4.7 −0.1 −5.8 Erk5 −9.0 −13.8 −11.4 −14.2 FER −13.4−5.8 −7.7 −10.0 FER 1.8 −5.3 −4.8 0.1 FES −15.6 −20.9 −13.3 −15.0 FGR87.0 94.7 86.0 87.8 FRAP 4.9 −3.5 −5.2 8.6 FRK 87.5 93.3 95.3 84.0 FYN,SRC, YES 97.4 98.4 97.9 88.1 GCK −13.9 −12.2 2.0 −10.9 GCK 11.6 −4.1 2.4−22.5 GCN2 −11.0 −13.3 −20.3 −6.2 GCN2 −5.7 −6.3 −13.6 −4.1 GSK3A −10.5−11.3 −14.2 −11.8 GSK3B 0.7 −1.9 −10.7 −5.1 HPK1 0.4 23.4 32.8 23.0 HPK126.6 19.8 24.6 12.1 IKKa 6.4 −3.5 −4.2 −2.1 IKKb 3.1 10.9 23.2 15.1 IKKb4.4 −29.2 −24.5 −3.2 IKKe 2.2 0.4 −5.9 −1.0 IKKe, TBK1 −38.7 −10.7 5.5−27.2 ILK 6.7 17.1 19.4 13.8 ILK −19.1 28.2 36.6 −0.3 IRAK1 20.3 19.013.6 26.3 IRAK4 17.8 7.6 11.9 15.9 IRAK4 25.9 25.6 26.7 18.5 IRE1 −44.3−15.7 −1.5 −29.5 ITPK1 12.8 −17.5 −16.4 14.0 JAK1 −5.7 7.5 −1.9 5.4 JAK1domain2 −17.6 −17.9 −22.7 −19.8 JAK1 domain2 −1.2 −6.4 −11.2 −2.3 JAK3domain2 −30.8 −66.2 −109.0 −83.2 JAK3 domain2 −19.2 −32.6 −49.6 −36.2JNK1, JNK2, JNK3 6.3 −4.8 −9.5 −23.5 KHS1 −2.1 −5.9 −8.4 −0.6 KSR1, KSR2−8.9 −10.1 −8.8 −8.7 LATS2 −9.2 −6.6 10.6 −2.9 LCK 96.1 96.5 94.8 92.4LKB1 −4.5 1.2 −1.8 −1.2 LOK −4.1 −15.0 −14.7 −5.5 LOK −27.4 2.9 19.2−15.4 LRRK2 −5.7 −9.6 −12.2 −20.9 LYN >97 >97 >97 88.1LYN >90 >90 >90 >90 MAP2K1 −31.6 −3.7 1.0 −23.4 MAP2K1, MAP2K2 9.9 7.49.8 20.5 MAP2K1, MAP2K2 −4.8 −4.1 −2.3 −2.2 MAP2K3 −12.3 −2.9 5.7 −19.5MAP2K3 −18.8 −14.1 −23.1 −15.9 MAP2K4 −48.8 −25.3 −8.5 −28.3 MAP2K4 −6.9−14.5 −6.1 1.2 MAP2K5 33.0 37.6 19.2 14.8 MAP2K5 −13.3 45.7 30.9 −10.9MAP2K6 −18.0 5.9 3.8 −8.3 MAP2K6 −10.7 2.5 −8.3 −12.6 MAP2K7 −10.1 11.2−7.5 −0.6 MAP3K1 18.4 7.9 15.5 −1.2 MAP3K15, MAP3K5, MAP3K6 2.8 4.0 2.27.5 MAP3K2 12.1 4.9 3.5 21.3 MAP3K2, MAP3K3 24.8 15.6 19.4 17.1 MAP3K3−0.7 42.8 7.9 13.7 MAP3K4 −20.5 −24.2 12.8 −23.9 MAP3K5 −10.7 −9.3 −0.7−22.9 MAP3K6 10.9 −21.3 −8.1 18.9 MAPKAPK3 7.0 0.9 0.5 6.2 MARK1, MARK217.1 7.9 14.6 20.9 MARK2 3.6 7.7 12.1 15.4 MARK2, MARK3 −31.5 −11.0 7.5−10.1 MARK3 13.5 12.7 7.8 18.4 MARK3, MARK4 19.1 20.7 5.8 17.4 MARK4−0.5 4.9 −0.4 12.8 MARK4 12.4 14.1 1.6 9.7 MAST1, MAST2 −62.1 −35.0−32.5 −81.3 MAST3 2.0 −1.6 −8.3 3.8 MASTL −2.9 −10.9 −16.9 −16.7 MASTL−0.3 −13.8 −9.5 −8.2 MELK −11.7 −11.0 −10.0 4.2 MLK3 −27.2 −4.6 11.7−18.0 MLKL −9.4 −6.3 −17.5 −0.8 MPSK1 −17.4 −15.5 −10.0 −4.0 MPSK1 −79.7−39.7 −25.7 −39.6 MSK1 domain1 −15.8 −40.5 −45.5 −35.0 MSK1, MSK2domain1 −28.9 −40.4 −29.7 −37.4 MSK2 domain1 −9.6 −45.3 −47.7 −33.9 MST17.0 3.0 2.4 13.2 MST1, MST2 3.8 9.5 8.7 3.1 MST2 12.3 6.5 4.3 14.7 MST3−17.6 5.0 −1.5 5.9 MST3 5.2 −5.6 −7.7 2.0 MST4 −13.2 11.6 −0.8 21.1MST4, YSK1 20.5 12.7 19.3 9.2 MYO3A, MYO3B 15.9 17.2 23.1 12.9 NDR1−38.8 −18.1 −0.8 −21.2 NDR1 −4.7 4.5 2.2 3.9 NDR2 −42.0 −20.0 1.9 −11.0NDR2 7.2 7.4 9.1 18.7 NEK1 7.3 11.4 12.8 14.9 NEK2 22.3 8.5 −3.0 −6.0NEK3 3.5 15.6 3.2 8.1 NEK4 12.3 7.9 15.2 18.5 NEK6, NEK7 3.7 −8.4 −11.0−0.2 NEK7 −7.7 10.0 −1.0 −8.5 NEK8 14.6 12.2 13.1 6.5 NEK9 −0.1 2.5 −1.3−1.0 NEK9 4.4 1.1 −0.3 −0.1 NLK 6.7 4.2 6.1 3.7 OSR1 26.7 22.0 27.9 16.4p38a 47.9 69.8 79.0 36.4 p38a 6.2 51.2 30.5 −8.7 p38b −29.6 −1.5 12.0−19.0 p38d, p38g −2.7 1.7 3.3 −6.6 p70S6K −102.3 −70.1 −36.8 −65.4p70S6Kb −72.4 −42.7 −22.7 −57.1 PAN3 −29.0 −0.2 18.3 −7.0 PCTAIRE1 19.038.2 32.9 38.4 PCTAIRE1, PCTAIRE3 12.7 14.9 19.8 11.4 PCTAIRE2 13.4 9.98.5 7.7 PCTAIRE2, PCTAIRE3 27.9 27.0 28.8 31.8 PEK −44.9 2.6 3.3 −31.0PFTAIRE1 15.3 19.1 22.1 24.3 PFTAIRE1 6.3 4.8 7.3 6.0 PHKg2 −15.6 0.66.4 −9.1 PI4KA, PI4KAP2 −37.7 −17.4 −9.9 −45.7 PI4KB 20.0 36.0 44.2 7.2PI4KB 16.7 35.3 41.9 13.7 PIK3C2B −5.8 39.9 12.5 −5.8 PIK3C3 −14.1 −7.4−2.6 −4.7 PIK3C3 −5.5 10.9 8.6 −11.6 PIK3CB −61.3 −42.6 −10.1 −64.9PIK3CD −14.5 −19.1 −16.2 −9.5 PIK3CG −46.3 −51.9 −55.4 −45.9 PIP4K2A−8.9 −36.0 −37.8 −20.5 PIP4K2A −21.4 −7.4 9.0 1.3 PIP4K2C 71.0 70.9 97.6−17.6 PIP4K2C 43.0 60.1 85.7 −32.0 PIP5K3 14.5 4.3 4.2 16.3 PITSLRE−13.6 −9.3 −16.1 −16.1 PKD1, PKD2 −4.7 −8.3 −15.3 −19.8 PKD2 12.9 10.08.7 12.7 PKN1 17.4 4.2 13.7 20.9 PKR −0.1 −2.8 −8.0 −3.2 PKR 16.9 21.921.3 22.3 PLK1 1.9 2.7 −7.8 0.5 PLK1 17.4 16.1 12.8 −0.2 PRP4 6.9 −4.1−10.7 6.9 PRPK −13.6 −3.8 3.7 −5.2 PYK2 6.7 16.6 20.3 12.5 PYK2 27.328.4 25.5 36.6 ROCK1 6.7 6.6 4.4 12.8 RSK1 domain1 −62.2 −97.5 −108.2−76.3 RSK1 domain1 −53.4 −75.8 −91.8 −76.3 RSK1 domain2 12.5 4.9 0.514.0 RSK1, RSK2, RSK3 domain1 −44.0 −58.3 −55.6 −52.0 RSK2 domain1 −90.2−128.5 −163.6 −132.7 RSK2 domain1 −72.7 −102.7 −122.4 −100.2 RSK2domain2 13.8 −0.3 −6.8 9.7 RSK3 16.8 12.6 2.9 22.3 RSK3 domain1 −26.9−48.6 −62.5 −58.4 RSK4 domain1 3.5 −13.5 −8.2 −22.4 RSKL1 10.7 29.7 35.013.7 SGK3 4.4 10.0 6.5 8.1 SGK3 8.2 −17.5 −5.4 −3.8 SLK −2.4 −21.1 −13.70.0 SLK 20.5 15.2 16.2 −3.6 SMG1 −2.4 −9.9 −8.5 3.1 SMG1 13.1 21.5 23.127.8 SNRK 35.3 40.7 45.1 47.8 SNRK 61.9 58.7 59.1 59.8SRC >90 >90 >90 >90 SRPK1 −2.1 1.2 −19.5 −4.7 SRPK1, SRPK2 −14.7 17.333.2 0.0 STK33 −23.0 21.1 29.8 11.0 STLK5 2.0 3.3 1.1 2.6 STLK5 −4.4−13.9 −4.0 3.8 STLK6 7.4 −16.3 −12.9 −0.8 SYK −2.2 −16.5 −12.5 −3.2 SYK12.5 5.7 12.4 16.1 TAK1 27.8 14.5 9.7 25.6 TAO1, TAO3 7.6 −1.8 −8.7−17.2 TAO2 −7.0 −18.0 −4.9 −17.9 TBK1 −34.8 −39.7 −2.9 −30.2 TEC 68.785.1 79.5 91.5 TEC 73.7 58.6 71.1 80.8 TLK1 2.2 1.8 −12.5 7.1 TLK1 8.25.5 5.7 5.7 TLK2 8.7 7.3 9.4 7.3 TYK2 domain2 −3.8 −46.4 −44.6 −19.0ULK1 16.2 19.3 16.1 19.7 ULK3 22.5 15.5 23.7 22.4 ULK3 21.9 18.4 11.322.8 VRK2 −30.6 −2.3 3.6 5.2 Wnk1, Wnk2 7.8 −8.6 −16.4 −3.8 Wnk1, Wnk2,Wnk3 17.5 10.4 1.7 2.4 Wnk1, Wnk2, Wnk4 −0.5 −6.6 −16.3 −8.1 YSK1 −58.5−19.9 −29.2 −27.4 ZC1/HGK, ZC2/TNIK, ZC3/MINK 3.3 6.2 13.6 4.2 ZC2/TNIK48.8 −1.5 19.0 −10.0

Example 25. Ambit KINOMESCAN Assay of Compounds I-2 and I-3

Each of compounds I-2 (1 μM) and I-3 (1 μM) was subject to an AmbitKINOMESCAN (DISCOVERRX) assay according to the protocols described inFabian et al. (Nat. Biotechnol. 2005, 23(3): 329-336) and/or Davis etal. (Nat. Biotechnol. 2011, 29(11): 1046-1051) to determine theinhibition against a broad panel of kinases. Exemplary results are shownin Tables 4 and 5.

TABLE 4 Exemplary KINOMESCAN assay results of compound I-3. % changecompared to Kinase ENTREZ gene symbol control ABL1(H396P)-phosphorylatedABL1 0 ABL1-phosphorylated ABL1 0 BLK BLK 0 EPHA4 EPHA4 0 EPHB2 EPHB2 0EPHB3 EPHB3 0 EPHB4 EPHB4 0 FGR FGR 0 JAK3(JH1domain-catalytic) JAK3 0KIT KIT 0 KIT(L576P) KIT 0 KIT(V559D) KIT 0 PDGFRB PDGFRB 0 SRC SRC 0YES YES1 0 ABL1(H396P)-nonphosphorylated ABL1 0.05 BTK BTK 0.05ABL1(Y253F)-phosphorylated ABL1 0.1 ABL1-nonphosphorylated ABL1 0.1 FRKFRK 0.1 LYN LYN 0.1 ABL1(Q252H)-nonphosphorylated ABL1 0.15 DDR1 DDR10.15 EPHB1 EPHB1 0.2 ERBB4 ERBB4 0.2 p38-alpha MAPK14 0.2 ABL2 ABL2 0.25ABL1(Q252H)-phosphorylated ABL1 0.3 SIK SIK1 0.4 EPHA8 EPHA8 0.45 MEK5MAP2K5 0.45 ABL1(E255K)-phosphorylated ABL1 0.5ABL1(F317L)-nonphosphorylated ABL1 0.5 FYN FYN 0.5 LCK LCK 0.55 EPHA2EPHA2 0.6 HCK HCK 0.6 ABL1(M351T)-phosphorylated ABL1 0.7 TXK TXK 0.7EGFR(L858R) EGFR 0.75 EGFR(L861Q) EGFR 0.8 ERBB2 ERBB2 0.8 ERBB3 ERBB30.8 EPHA5 EPHA5 0.85 ABL1(F317I)-nonphosphorylated ABL1 1.2EGFR(L747-E749del, A750P) EGFR 1.4 CSK CSK 1.6 EPHA1 EPHA1 1.6ABL1(F317L)-phosphorylated ABL1 2 BRAF(V600E) BRAF 2.1 EGFR EGFR 2.6KIT-autoinhibited KIT 2.6 EGFR(E746-A750del) EGFR 2.9CSF1R-autoinhibited CSF1R 3.2 CSF1R CSF1R 3.3 TEC TEC 3.3EGFR(L747-S752del, P753S) EGFR 3.6 EGFR(L747-T751del, Sins) EGFR 4.2EGFR(S752-I759del) EGFR 4.6 EPHB6 EPHB6 4.6 BMX BMX 4.9ABL1(F317I)-phosphorylated ABL1 5.2 PDGFRA PDGFRA 6.5 BRAF BRAF 6.8EGFR(G719S) EGFR 7.6 PFCDPK1(P. falciparum) CDPK1 8.1 DDR2 DDR2 8.4 BRKPTK6 9.3 NLK NLK 9.4 KIT(A829P) KIT 10 GAK GAK 11 SRMS SRMS 12EGFR(G719C) EGFR 14 KIT(D816V) KIT 14 KIT(D816H) KIT 23 KIT(V559D,V654A) KIT 25 LIMK1 LIMK1 25 STK36 STK36 25 RAF1 RAF1 26TYK2(JH2domain-pseudokinase) TYK2 26 RIPK2 RIPK2 31 PIK4CB PI4KB 36TYRO3 TYRO3 41 EGFR(L858R, T790M) EGFR 42 TNK2 TNK2 43 TNNI3K TNNI3K 44BMPR1B BMPR1B 45 PIK3C2B PIK3C2B 47 PKMYT1 PKMYT1 47 ADCK3 CABC1 49EPHA3 EPHA3 49 NEK11 NEK11 49 QSK KIAA0999 50 PAK3 PAK3 51 RPS6KA5(Kin.Dom. 2-C-terminal) RPS6KA5 52 EGFR(T790M) EGFR 56 MARK3 MARK3 57 NDR2STK38L 58 SBK1 SBK1 58 HPK1 MAP4K1 61 SGK SGK1 61 ERK4 MAPK4 62 CAMK1CAMK1 63 p38-beta MAPK11 63 TRPM6 TRPM6 63 NEK6 NEK6 64 SRPK2 SRPK2 64LIMK2 LIMK2 65 PIP5K1C PIP5K1C 65 DMPK2 CDC42BPG 66 MINK MINK1 66 TAOK2TAOK2 67 BUB1 BUB1 68 PRKR EIF2AK2 69 ABL1(T315I)-phosphorylated ABL1 70CSNK2A2 CSNK2A2 70 VRK2 VRK2 70 AURKC AURKC 71 STK39 STK39 71 PIM2 PIM272 DYRK1B DYRK1B 74 DYRK2 DYRK2 74 NDR1 STK38 74 CDK9 CDK9 75 ROCK2ROCK2 75 ACVRL1 ACVRL1 76 ALK(L1196M) ALK 76 AXL AXL 76 ERN1 ERN1 76PLK2 PLK2 76 SGK2 SGK2 76 RIOK2 RIOK2 77 AMPK-alpha2 PRKAA2 78 CDC2L1CDK11B 78 CDKL2 CDKL2 78 TTK TTK 78 AURKA AURKA 80 DAPK2 DAPK2 80 MAP3K1MAP3K1 80 MARK2 MARK2 80 MARK4 MARK4 80 AKT3 AKT3 81 CAMK2B CAMK2B 81CDKL3 CDKL3 81 CTK MATK 81 JNK1 MAPK8 81 PCTK2 CDK17 81 PKN1 PKN1 81PRKD3 PRKD3 81 SYK SYK 81 ACVR2A ACVR2A 82 JAK2(JH1domain-catalytic)JAK2 82 MELK MELK 82 PLK4 PLK4 82 RIOK1 RIOK1 82 ALK ALK 83 CAMK2ACAMK2A 83 CDK11 CDK19 83 HUNK HUNK 83 PLK1 PLK1 83 ALK(C1156Y) ALK 84CAMK4 CAMK4 84 CHEK1 CHEK1 84 DAPK3 DAPK3 84 DCAMKL1 DCLK1 84 FLT3 FLT384 NIK MAP3K14 84 NIM1 MGC42105 84 PAK6 PAK6 84 YANK1 STK32A 84 CLK4CLK4 85 MKK7 MAP2K7 85 MLK3 MAP3K11 85 NEK1 NEK1 85 PIK3CD PIK3CD 85PKAC-alpha PRKACA 85 FLT1 FLT1 86 IKK-beta IKBKB 86 MYO3B MYO3B 86 RETRET 86 RIPK5 DSTYK 86 ULK1 ULK1 86 ICK ICK 87 NEK5 NEK5 87 PDPK1 PDPK187 YSK1 STK25 87 CIT CIT 88 FGFR2 FGFR2 88 HASPIN GSG2 88 LZK MAP3K13 88MRCKA CDC42BPA 88 PRKCH PRKCH 88 RPS6KA5(Kin. Dom. 1-N-terminal) RPS6KA588 TESK1 TESK1 88 ERK3 MAPK6 89 MEK6 MAP2K6 89 PIK3CA(I800L) PIK3CA 89PIM3 PIM3 89 ROCK1 ROCK1 89 RSK3(Kin. Dom. 1-N-terminal) RPS6KA2 89STK16 STK16 89 BIKE BMP2K 90 CAMK1D CAMK1D 90 ERK5 MAPK7 90 JNK2 MAPK990 NEK10 NEK10 90 PRKCI PRKCI 90 RIOK3 RIOK3 90 ROS1 ROS1 90 TAK1 MAP3K790 ASK1 MAP3K5 91 JNK3 MAPK10 91 MAP4K2 MAP4K2 91 PIP5K1A PIP5K1A 91PKNB(M. tuberculosis) pknB 91 PRKG2 PRKG2 91 RSK1(Kin. Dom.1-N-terminal) RPS6KA1 91 TAOK3 TAOK3 91 TYK2(JH1domain-catalytic) TYK291 ULK2 ULK2 91 YANK3 STK32C 91 ADCK4 ADCK4 92 BMPR1A BMPR1A 92 CAMK2DCAMK2D 92 DCAMKL3 DCLK3 92 LATS2 LATS2 92 MET(Y1235D) MET 92 MLK1 MAP3K992 PCTK3 CDK18 92 SNRK SNRK 92 TRKB NTRK2 92 CDC2L2 CDC2L2 93 CDKL1CDKL1 93 CSNK1G2 CSNK1G2 93 DCAMKL2 DCLK2 93 FES FES 93 FGFR1 FGFR1 93INSR INSR 93 IRAK1 IRAK1 93 IRAK3 IRAK3 93 LATS1 LATS1 93 MARK1 MARK1 93MAST1 MAST1 93 MYLK MYLK 93 PAK2 PAK2 93 TNIK TNIK 93 CDK7 CDK7 94MAP3K3 MAP3K3 94 MET MET 94 MST2 STK3 94 PHKG2 PHKG2 94 PRKD1 PRKD1 94SLK SLK 94 TBK1 TBK1 94 TLK2 TLK2 94 ZAK ZAK 94 ACVR2B ACVR2B 95 AKT1AKT1 95 BRSK2 BRSK2 95 CDK4-cyclinD3 CDK4 95 CLK3 CLK3 95 CSNK1A1LCSNK1A1L 95 CSNK1G3 CSNK1G3 95 ERK1 MAPK3 95 HIPK1 HIPK1 95 MAP3K4MAP3K4 95 MLK2 MAP3K10 95 NEK3 NEK3 95 PAK1 PAK1 95 PFTAIRE2 CDK15 95PIM1 PIM1 95 PRKCD PRKCD 95 SgK110 SgK110 95 WNK1 WNK1 95 CLK2 CLK2 96CSNK1E CSNK1E 96 GRK7 GRK7 96 IRAK4 IRAK4 96 MAP4K4 MAP4K4 96 MAP4K5MAP4K5 96 MYO3A MYO3A 96 NEK2 NEK2 96 PIK3CA(H1047Y) PIK3CA 96 SRPK1SRPK1 96 STK33 STK33 96 TRKC NTRK3 96 YANK2 STK32B 96 CAMK1G CAMK1G 97CAMK2G CAMK2G 97 CAMKK1 CAMKK1 97 CHEK2 CHEK2 97 EIF2AK1 EIF2AK1 97 GRK1GRK1 97 GSK3A GSK3A 97 HIPK4 HIPK4 97 LOK STK10 97 MST1 STK4 97 PAK7PAK7 97 PIK3C2G PIK3C2G 97 PLK3 PLK3 97 RSK2(Kin. Dom. 1-N-terminal)RPS6KA3 97 RSK3(Kin. Dom. 2-C-terminal) RPS6KA2 97 RSK4(Kin. Dom.2-C-terminal) RPS6KA6 97 S6K1 RPS6KB1 97 SRPK3 SRPK3 97 TGFBR1 TGFBR1 97WEE2 WEE2 97 AMPK-alpha1 PRKAA1 98 ASK2 MAP3K6 98 CASK CASK 98 CDK8 CDK898 CSNK2A1 CSNK2A1 98 DMPK DMPK 98 FLT3(ITD) FLT3 98 ITK ITK 98 MAP3K2MAP3K2 98 MKNK2 MKNK2 98 NEK7 NEK7 98 OSR1 OXSR1 98 PRKCQ PRKCQ 98 SIK2SIK2 98 TAOK1 TAOK1 98 ULK3 ULK3 98 CDK4-cyclinD1 CDK4 99 CSNK1D CSNK1D99 ERK8 MAPK15 99 FER FER 99 FGFR3(G697C) FGFR3 99 LRRK2(G2019S) LRRK299 PFTK1 CDK14 99 PHKG1 PHKG1 99 PIK3CA(C420R) PIK3CA 99 RET(M918T) RET99 TRKA NTRK1 99 AAK1 AAK1 100 ABL1(T315I)-nonphosphorylated ABL1 100ACVR1 ACVR1 100 ACVR1B ACVR1B 100 AKT2 AKT2 100 ANKK1 ANKK1 100 ARK5NUAK1 100 AURKB AURKB 100 BMPR2 BMPR2 100 BRSK1 BRSK1 100 CAMKK2 CAMKK2100 CDC2L5 CDK13 100 CDK2 CDK2 100 CDK3 CDK3 100 CDK5 CDK5 100 CDKL5CDKL5 100 CLK1 CLK1 100 CSNK1A1 CSNK1A1 100 CSNK1G1 CSNK1G1 100 DAPK1DAPK1 100 DLK MAP3K12 100 DRAK1 STK17A 100 DRAK2 STK17B 100 DYRK1ADYRK1A 100 EPHA6 EPHA6 100 EPHA7 EPHA7 100 ERK2 MAPK1 100 FAK PTK2 100FGFR3 FGFR3 100 FGFR4 FGFR4 100 FLT3(D835H) FLT3 100 FLT3(D835Y) FLT3100 FLT3(K663Q) FLT3 100 FLT3(N841I) FLT3 100 FLT3(R834Q) FLT3 100FLT3-autoinhibited FLT3 100 FLT4 FLT4 100 GCN2(Kin. Dom. 2, S808G)EIF2AK4 100 GRK4 GRK4 100 GSK3B GSK3B 100 HIPK2 HIPK2 100 HIPK3 HIPK3100 IGF1R IGF1R 100 IKK-alpha CHUK 100 IKK-epsilon IKBKE 100 INSRR INSRR100 JAK1(JH1domain-catalytic) JAK1 100 JAK1(JH2domain-pseudokinase) JAK1100 KIT(V559D, T670I) KIT 100 LKB1 STK11 100 LRRK2 LRRK2 100 LTK LTK 100MAK MAK 100 MAP3K15 MAP3K15 100 MAP4K3 MAP4K3 100 MAPKAPK2 MAPKAPK2 100MAPKAPK5 MAPKAPK5 100 MEK1 MAP2K1 100 MEK2 MAP2K2 100 MEK3 MAP2K3 100MEK4 MAP2K4 100 MERTK MERTK 100 MET(M1250T) MET 100 MKNK1 MKNK1 100 MLCKMYLK3 100 MRCKB CDC42BPB 100 MST1R MST1R 100 MST3 STK24 100 MST4 MST4100 MTOR MTOR 100 MUSK MUSK 100 MYLK2 MYLK2 100 MYLK4 MYLK4 100 NEK4NEK4 100 NEK9 NEK9 100 p38-delta MAPK13 100 p38-gamma MAPK12 100 PAK4PAK4 100 PCTK1 CDK16 100 PFPK5(P. falciparum) MAL13P1.279 100 PIK3CAPIK3CA 100 PIK3CA(E542K) PIK3CA 100 PIK3CA(E545A) PIK3CA 100PIK3CA(E545K) PIK3CA 100 PIK3CA(H1047L) PIK3CA 100 PIK3CA(M1043I) PIK3CA100 PIK3CA(Q546K) PIK3CA 100 PIK3CB PIK3CB 100 PIK3CG PIK3CG 100 PIP5K2BPIP4K2B 100 PIP5K2C PIP4K2C 100 PKAC-beta PRKACB 100 PKN2 PKN2 100 PRKCEPRKCE 100 PRKD2 PRKD2 100 PRKG1 PRKG1 100 PRKX PRKX 100 PRP4 PRPF4B 100PYK2 PTK2B 100 RET(V804L) RET 100 RET(V804M) RET 100 RIPK1 RIPK1 100RIPK4 RIPK4 100 RPS6KA4(Kin. Dom. 1-N-terminal) RPS6KA4 100 RPS6KA4(Kin.Dom. 2-C-terminal) RPS6KA4 100 RSK1(Kin. Dom. 2-C-terminal) RPS6KA1 100RSK2(Kin. Dom. 2-C-terminal) RPS6KA3 100 RSK4(Kin. Dom. 1-N-terminal)RPS6KA6 100 SGK3 SGK3 100 SNARK NUAK2 100 STK35 STK35 100 TGFBR2 TGFBR2100 TIE1 TIE1 100 TIE2 TEK 100 TLK1 TLK1 100 TNK1 TNK1 100 TSSK1B TSSK1B100 VEGFR2 KDR 100 WEE1 WEE1 100 WNK3 WNK3 100 YSK4 YSK4 100 ZAP70 ZAP70100

TABLE 5 Exemplary KINOMESCAN assay results of compound I-2. % changecompared to Kinase control ABL1(F317L)-nonphosphorylated 0ABL1(H396P)-nonphosphorylated 0 ABL1(H396P)-phosphorylated 0ABL1-phosphorylated 0 BLK 0 BTK 0 EPHA4 0 EPHB2 0 EPHB3 0 EPHB4 0JAK3(JH1domain-catalytic) 0 KIT 0 KIT(L576P) 0 KIT(V559D) 0 LYN 0 PDGFRB0 SRC 0 YES 0 ABL1-nonphosphorylated 0.05 ABL1(Y253F)-phosphorylated 0.1ERBB3 0.1 FGR 0.1 FRK 0.1 p38-alpha 0.1 ABL1(F317I)-nonphosphorylated0.15 DDR1 0.2 EPHA2 0.2 ABL1(Q252H)-phosphorylated 0.25 MEK5 0.25ABL1(Q252H)-nonphosphorylated 0.3 ABL2 0.3 FYN 0.3 EPHB1 0.35ABL1(E255K)-phosphorylated 0.45 ABL1(F317L)-phosphorylated 0.5 EPHA1 0.5ABL1(M351T)-phosphorylated 0.6 ERBB4 0.6 TXK 0.6 LCK 0.65 EPHA8 0.75 SIK0.8 HCK 0.9 EPHA5 0.95 EGFR(L861Q) 1.3 CSF1R-autoinhibited 1.4BRAF(V600E) 1.6 BRK 1.6 CSK 1.6 KIT(D816V) 1.7 KIT-autoinhibited 1.8EGFR(L747-T751del, Sins) 2 EGFR(L858R) 2 EGFR(L747-E749del, A750P) 2.2CSF1R 2.6 STK36 3.5 BMX 3.6 EGFR(L747-S752del, P753S) 3.6 TEC 3.6EGFR(E746-A750del) 3.7 BRAF 4.4 PDGFRA 4.5 ABL1(F317I)-phosphorylated5.4 EGFR 5.6 KIT(A829P) 5.8 KIT(V559D, V654A) 7.2 ERBB2 7.5 SRMS 7.6EPHB6 7.7 DDR2 8.6 ADCK3 9.2 BMPR1B 10 GAK 11 NLK 11 KIT(D816H) 14 RIPK214 TNNI3K 16 EGFR(G719S) 17 EGFR(S752-I759del) 17 EGFR(G719C) 23PFCDPK1(P. falciparum) 24 RAF1 26 TYK2(JH2domain-pseudokinase) 28 TNK231 QSK 36 TYRO3 41 EPHA3 47 EGFR(L858R, T790M) 48 EGFR(T790M) 48 TGFBR150 DMPK2 51 HPK1 51 LIMK2 51 LIMK1 52 ACVRL1 54 SBK1 54 SGK 56 CSNK2A257 PKMYT1 59 SgK110 59 TESK1 60 TRPM6 61 p38-beta 62 NDR1 63JAK2(JH1domain-catalytic) 65 MRCKA 65 TAOK2 65 CTK 67 INSR 67 MEK1 67ACVR1B 68 ABL1(T315I)-phosphorylated 69 MST2 69 MAP3K1 70 MINK 71ALK(L1196M) 72 PFTK1 72 SGK2 72 AURKA 73 CDK3 73 FGFR2 73 PKNB(M.tuberculosis) 73 PLK4 73 RSK1(Kin. Dom. 1-N-terminal) 73 TSSK1B 73 ACVR174 IKK-beta 75 PAK3 75 ACVR2A 76 IRAK4 76 PIK3CA(I800L) 76 ACVR2B 78MEK2 78 MAP3K3 79 PIK3CD 79 ULK1 79 OSR1 81 PRKD3 81 TAOK3 81 MAP4K5 82MEK6 82 ERN1 83 MAP3K4 83 NEK11 83 PIK3CA(Q546K) 83 YANK3 83 CAMK2B 84CSNK1E 84 IRAK1 84 MELK 84 PIK3CA(H1047L) 84 PIM2 84 PKN2 84 BUB1 85GCN2(Kin. Dom. 2, S808G) 85 MYLK 85 PKAC-alpha 85 YSK1 85 CAMK2A 86DAPK2 86 ICK 86 PIK3C2B 86 STK33 86 SYK 86 DCAMKL1 87 MAP4K2 87 ZAK 87AKT2 88 CDC2L1 88 CDKL2 88 CHEK1 88 DYRK2 88 MKK7 88 NEK1 88 ROCK1 88CAMK1G 89 DAPK3 89 MLK1 89 MRCKB 89 PRKR 89 TBK1 89TYK2(JH1domain-catalytic) 89 ULK2 89 AKT3 90 AURKC 90 CDK9 90 CSNK2A1 90ERK4 90 MERTK 90 RIOK1 90 CAMK1 91 CAMK2D 91 CAMK2G 91 ERK5 91 FGFR1 91MARK4 91 NIK 91 SRPK1 91 AMPK-alpha2 92 ASK2 92 CDC2L2 92 CLK1 92FLT3(ITD) 92 MAP3K15 92 PAK2 92 PIK3C2G 92 PIK3CA(E542K) 92 PIP5K1A 92PKAC-beta 92 PLK1 92 PLK2 92 RET(M918T) 92 RIOK2 92 SIK2 92 SRPK2 92STK39 92 CDK8 93 FLT1 93 HIPK1 93 IKK-alpha 93 IRAK3 93 MYO3A 93 MYO3B93 NEK10 93 NIM1 93 PAK6 93 PRKD1 93 RSK3(Kin. Dom. 1-N-terminal) 93TAOK1 93 WEE1 93 ALK(C1156Y) 94 ANKK1 94 CDK4-cyclinD3 94 CDK7 94 CLK494 DYRK1B 94 GRK1 94 JNK1 94 LRRK2 94 MARK3 94 NEK3 94 PIK3CA(E545K) 94PRKCI 94 PRKCQ 94 RPS6KA5(Kin. Dom. 2-C-terminal) 94 TGFBR2 94 TRKB 94VRK2 94 ABL1(T315I)-nonphosphorylated 95 ADCK4 95 AKT1 95 FLT4 95 HIPK395 MET(Y1235D) 95 PRP4 95 RIPK4 95 ROCK2 95 RSK2(Kin. Dom. 1-N-terminal)95 TAK1 95 ASK1 96 AURKB 96 AXL 96 CAMK4 96 CDK4-cyclinD1 96 CSNK1G3 96FLT3(K663Q) 96 INSRR 96 LOK 96 MAP3K2 96 MAP4K4 96 NDR2 96 NEK5 96 PAK796 PHKG2 96 PIK3CA(M1043I) 96 PRKCD 96 RPS6KA4(Kin. Dom. 2-C-terminal)96 SLK 96 AAK1 97 ALK 97 CAMKK2 97 CHEK2 97 CSNK1G2 97 DCAMKL3 97 ERK197 ERK8 97 FLT3(D835Y) 97 GRK7 97 HIPK2 97 JNK3 97 LZK 97 MARK1 97 MET97 PCTK1 97 PIM1 97 PIM3 97 PRKCH 97 ROS1 97 TLK2 97 TNIK 97 ULK3 97CDK11 98 CDKL3 98 DCAMKL2 98 DLK 98 DMPK 98 FES 98 MAST1 98 MUSK 98MYLK4 98 PDPK1 98 PIP5K2B 98 RET(V804L) 98 RIOK3 98 RPS6KA5(Kin. Dom.1-N-terminal) 98 TRKA 98 ARK5 99 FGFR3 99 MEK3 99 MST1R 99 PCTK3 99PIP5K1C 99 PLK3 99 PRKG2 99 STK16 99 STK35 99 TRKC 99 ZAP70 99AMPK-alpha1 100 BIKE 100 BMPR1A 100 BMPR2 100 BRSK1 100 BRSK2 100 CAMK1D100 CAMKK1 100 CASK 100 CDC2L5 100 CDK2 100 CDK5 100 CDKL1 100 CDKL5 100CIT 100 CLK2 100 CLK3 100 CSNK1A1 100 CSNK1A1L 100 CSNK1D 100 CSNK1G1100 DAPK1 100 DRAK1 100 DRAK2 100 DYRK1A 100 EIF2AK1 100 EPHA6 100 EPHA7100 ERK2 100 ERK3 100 FAK 100 FER 100 FGFR3(G697C) 100 FGFR4 100 FLT3100 FLT3(D835H) 100 FLT3(N841I) 100 FLT3(R834Q) 100 FLT3-autoinhibited100 GRK4 100 GSK3A 100 GSK3B 100 HASPIN 100 HIPK4 100 HUNK 100 IGF1R 100IKK-epsilon 100 ITK 100 JAK1(JH1domain-catalytic) 100JAK1(JH2domain-pseudokinase) 100 JNK2 100 KIT(V559D, T670I) 100 LATS1100 LATS2 100 LKB1 100 LRRK2(G2019S) 100 LTK 100 MAK 100 MAP4K3 100MAPKAPK2 100 MAPKAPK5 100 MARK2 100 MEK4 100 MET(M1250T) 100 MKNK1 100MKNK2 100 MLCK 100 MLK2 100 MLK3 100 MST1 100 MST3 100 MST4 100 MTOR 100MYLK2 100 NEK2 100 NEK4 100 NEK6 100 NEK7 100 NEK9 100 p38-delta 100p38-gamma 100 PAK1 100 PAK4 100 PCTK2 100 PFPK5(P. falciparum) 100PFTAIRE2 100 PHKG1 100 PIK3CA 100 PIK3CA(C420R) 100 PIK3CA(E545A) 100PIK3CA(H1047Y) 100 PIK3CB 100 PIK3CG 100 PIK4CB 100 PIP5K2C 100 PKN1 100PRKCE 100 PRKD2 100 PRKG1 100 PRKX 100 PYK2 100 RET 100 RET(V804M) 100RIPK1 100 RIPK5 100 RPS6KA4(Kin. Dom. 1-N-terminal) 100 RSK1(Kin. Dom.2-C-terminal) 100 RSK2(Kin. Dom. 2-C-terminal) 100 RSK3(Kin. Dom.2-C-terminal) 100 RSK4(Kin. Dom. 1-N-terminal) 100 RSK4(Kin. Dom.2-C-terminal) 100 S6K1 100 SGK3 100 SNARK 100 SNRK 100 SRPK3 100 TIE1100 TIE2 100 TLK1 100 TNK1 100 TTK 100 VEGFR2 100 WEE2 100 WNK1 100 WNK3100 YANK1 100 YANK2 100 YSK4 100

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

1-40. (canceled)
 41. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein: each instance ofR^(B1) is independently halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —OR^(b), —N(R^(b))₂, —SR^(b),—CN, —SCN, —C(═NR^(b))R^(b), —C(═NR^(b))OR^(b), —C(═NR^(b))N(R^(b))₂,—C(═O)R^(b), —C(═O)OR^(b), —C(═O)N(R^(b))₂, —NO₂, —NR^(b)C(═O)R^(b),—NR^(b)C(═O)OR^(b), —NR^(b)C(═O)N(R^(b))₂, —OC(═O)R^(b), —OC(═O)OR^(b),or —OC(═O)N(R^(b))₂; each instance of R^(b) is independently hydrogen,substituted or unsubstituted acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, a nitrogen protecting groupwhen attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two instances of R^(b) are joined to form asubstituted or unsubstituted, heterocyclic ring, or substituted orunsubstituted, heteroaryl ring; p is 0, 1, 2, 3, 4, or 5; L^(B) is—C(═O)—NR^(B2)— or —NR^(B2)—C(═O)—, wherein R^(B2) is hydrogen,substituted or unsubstituted, C₁₋₆ alkyl, or a nitrogen protectinggroup; R^(B3) is hydrogen, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —OR^(b), —N(R^(b))₂, —SR^(b),—CN, —SCN, —C(═NR^(b))R^(b), —C(═NR^(b))OR^(b), —C(═NR^(b))N(R^(b))₂,—C(═O)R^(b), —C(═O)OR^(b), —C(═O)N(R^(b))₂, —NO₂, —NR^(b)C(═O)R^(b),—NR^(b)C(═O)OR^(b), —NR^(b)C(═O)N(R^(b))₂, —OC(═O)R^(b), —OC(═O)OR^(b),or —OC(═O)N(R^(b))₂; R^(B4) is hydrogen, substituted or unsubstituted,C₁₋₆ alkyl, or a nitrogen protecting group; Ring B3 is a substituted orunsubstituted pyrazolyl ring; each instance of R^(B5) is independentlyhalogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(b), —N(R^(b))₂, —SR^(b), —CN, —SCN, —C(═NR^(b))R^(b),—C(═NR^(b))OR^(b), —C(═NR^(b))N(R^(b))₂, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)N(R^(b))₂, —NO₂, —NR^(b)C(═O)R^(b), —NR^(b)C(═O)OR^(b),—NR^(b)C(═O)N(R^(b))₂, —OC(═O)R^(b), —OC(═O)OR^(b), or —OC(═O)N(R^(b))₂;q is 0, 1, or 2; and R^(B6) is substituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —C(═O)R^(b), —C(═O)OR^(b), or —C(═O)N(R^(b))₂. 42.(canceled)
 43. The compound of claim 41, wherein the compound is of theformula:

or a pharmaceutically acceptable salt thereof. 44-46. (canceled)
 47. Thecompound of claim 41, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 48. (canceled)
 49. Thecompound of claim 41, or a pharmaceutically acceptable salt thereof,wherein Ring B1 is of the formula:


50. (canceled)
 51. The compound of claim 41, or a pharmaceuticallyacceptable salt thereof, wherein at least one instance of R^(B1) issubstituted or unsubstituted alkyl or halogen. 52-55. (canceled)
 56. Thecompound of claim 41, or a pharmaceutically acceptable salt thereof,wherein L^(B) is —C(═O)—NH—. 57-58. (canceled)
 59. The compound of claim41, or a pharmaceutically acceptable salt thereof, wherein R^(B3) ishydrogen.
 60. The compound of claim 41, or a pharmaceutically acceptablesalt thereof, wherein R^(B4) is hydrogen.
 61. The compound of claim 41,or a pharmaceutically acceptable salt thereof, wherein Ring B3 is of theformula:

wherein the nitrogen atom labeled with “1” is attached to R^(B6), andthe carbon atom labeled with “3” is attached to the nitrogen atom towhich R^(B4) is attached; or

wherein the nitrogen atom labeled with “1” is attached to R^(B6), andthe carbon atom labeled with “4” is attached to the nitrogen atom towhich R^(B4) is attached. 62-63. (canceled)
 64. The compound of claim41, or a pharmaceutically acceptable salt thereof, wherein R^(B6) issubstituted alkyl.
 65. (canceled)
 66. The compound of claim 41, or apharmaceutically acceptable salt thereof, wherein R^(B6) is substitutedor unsubstituted, 3- to 9-membered, monocyclic heterocyclyl comprisingzero, one, or two double bonds in the heterocyclic ring system, whereinone, two, or three atoms of the heterocyclic ring system areindependently nitrogen, oxygen, or sulfur.
 67. The compound of claim 41,or a pharmaceutically acceptable salt thereof, wherein R^(B7) is of theformula:

wherein: each instance of R^(B7) is independently hydrogen, halogen, orsubstituted or unsubstituted, C₁₋₆ alkyl; x is 0, 1, 2, 3, or 4; y is 1,2, 3, or 4; h is 1, 2, or 3; each instance of R^(B8) is independentlyhalogen, or substituted or unsubstituted, C₁₋₆ alkyl; g is an integerbetween 0 and 13, inclusive; and R^(B9) is hydrogen, substituted orunsubstituted, C₁₋₆ alkyl, substituted or unsubstituted, C₂₋₆ alkenyl,substituted or unsubstituted, C₂₋₆ alkynyl, substituted or unsubstitutedcarbocyclyl, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, a nitrogenprotecting group, or of any one of Formulae (ii-1) to (ii-42):

wherein: L³ is a bond or an optionally substituted C₁₋₄ hydrocarbonchain, optionally wherein one or more carbon units of the hydrocarbonchain are independently replaced with —O—, —S—, —NR^(L3a)—,—NR^(L3a)C(═O)—, —C(═O)NR^(L3a)—, —SC(═O)—, —C(═O)S—, —OC(═O)—,—C(═O)O—, —NR^(L3a)C(═S)—, —C(═S)NR^(L3a)—, trans-CR^(L3b)═CR^(L3b)—,cis-CR^(L3b)═CR^(L3b)—, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—,—S(═O)NR^(L3a)—, —NR^(L3a)S(═O)—, —S(═O)₂—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR^(L3a)—, or —NR^(L3a)S(═O)₂—, wherein R^(L3a) is hydrogen,substituted or unsubstituted, C₁₋₆ alkyl, or a nitrogen protectinggroup, and wherein each occurrence of R^(L3b) is independently selectedfrom the group consisting of hydrogen, halogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, ortwo R^(L3b) groups are joined to form an optionally substitutedcarbocyclic or optionally substituted heterocyclic ring; L⁴ is a bond oran optionally substituted C₁₋₄ hydrocarbon chain; R^(E1) is selectedfrom the group consisting of hydrogen, halogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl, —CN,—CH₂OR^(E1a), —CH₂N(R^(E1a))₂, —CH₂SR^(E1a), —OR^(E1a)—, —N(R^(E1a))₂,—Si(R^(E1a))₃, and —SR^(E1a), wherein each occurrence of R^(E1a) isindependently selected from the group consisting of hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or two R^(E1a) groups are joined to form anoptionally substituted heterocyclic ring; R^(E2) is selected from thegroup consisting of hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl, —CN,—CH₂OR^(E2a), —CH₂N(R^(E2a))₂, —CH₂SR^(E2a), —OR^(E2a), —N(R^(E2a))₂,and —SR^(E2a), wherein each occurrence of R^(E2a) is independentlyselected from the group consisting of hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, ortwo R^(E2a) groups are joined to form an optionally substitutedheterocyclic ring; R^(E3) is selected from the group consisting ofhydrogen, halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —CN, —CH₂OR^(E3a),—CH₂N(R^(E3a))₂, —CH₂SR^(E3a), —OR^(E3a), —N(R^(E3a))₂, and —SR^(E3a),wherein each occurrence of R^(E3a) is independently selected from thegroup consisting of hydrogen, optionally substituted alkyl, optionallysubstituted alkoxy, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or two R^(E3a) groups are joined to form anoptionally substituted heterocyclic ring; or R^(E1) and R^(E3), orR^(E2) and R^(E3), or R^(E1) and R^(E2) are joined to form an optionallysubstituted carbocyclic or optionally substituted heterocyclic ring;R^(E4) is a leaving group; R^(E5) is halogen; Y is O, S, or NR^(E6),wherein R^(E6) is hydrogen, substituted or unsubstituted, C₁₋₆ alkyl, ora nitrogen protecting group; a is 1 or 2; and each instance of z isindependently 0, 1, 2, 3, 4, 5, or
 6. 68-75. (canceled)
 76. The compoundof claim 67, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof, wherein R^(b) issubstituted or unsubstituted, C₂₋₆ alkenyl. 77-79. (canceled)
 80. Thecompound of claim 41, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof. 81-115. (canceled)
 116. Apharmaceutical composition comprising a compound of claim 41, or apharmaceutically acceptable salt thereof, and optionally apharmaceutically acceptable excipient.
 117. A method of treating aproliferative disease in a subject in need thereof, the methodcomprising administering to the subject in need thereof an effectiveamount of a compound of claim 41, or a pharmaceutically acceptable saltthereof. 118-131. (canceled)
 132. A method of inhibiting the activity ofa protein kinase in a subject in need thereof, the method comprisingadministering to the subject in need thereof an effective amount of acompound of claim 41, or a pharmaceutically acceptable salt thereof.133-137. (canceled)
 138. A method of inhibiting the activity of aprotein kinase in a cell, the method comprising contacting the cell withan effective amount of a compound of claim 41, or a pharmaceuticallyacceptable salt thereof. 139-142. (canceled)
 143. A method of inducingapoptosis in a cell, the method comprising contacting the cell with aneffective amount of a compound of claim 41, or a pharmaceuticallyacceptable salt thereof. 144-146. (canceled)
 147. A kit comprising: acompound of claim 41, or a pharmaceutically acceptable salt thereof; andinstructions for using the compound or pharmaceutically acceptable salt.